Hyperglycemia defined as fasting BGL above ___? Diagnostic of what?
126 mg/dL; diabetes mellitus
In glycolysis, how many ATP can be created?
Net 2, but pyruvate can be oxidized to make 34 more (36 total)
What is the Pasteur effect?
Aerobic conditions suppress glycolysis via allosteric inhibition of glycolytic enzymes by citrate and ATP.
What is the Warburg effect?
Many cancers exhibit high glyc. rate even with oxygen
Where is Warburg effect used in clinical detection?
Positron emission tomography (PET) scanning, where ingested glucose tracer FdG shows where glucose is being consumed (invasive cancer cells take much more than normal cells)
What is erythritol?
A 4C sugar alcohol used as artif. sweetener. Little metabolized, little energy release, no tooth decay. Absorbed in SI, excreted in urine, low flatulence.
What is Xylitol?
5C sugar alcohol used as natural sweetener - low glycemic index, no tooth decay, lower energy than sucrose with same sweetness. No bad aftertaste like some. Flatulence included.
What is Mannitol?
Sugar alcohol for energy storage by microorganisms and plants. Treats head trauma, kidney failure. Heart-lung machine primer, makes blood-brain barrier permeable to drugs. Inhaled solid treats CF by liquifying mucus. Half as sweet as sucrose with flatulence included.
What is sorbital?
Sugar alcohol used as sweetener in chewing gum, toothpaste, mouthwash. Also a laxative.
Omega-3 and omega-6 fatty acids
Last double bond 3 (linolenic acid) or 6 (linoleic, arachidonic acids) C's from end of chain.
Lipids in Respiratory distress syndrome
Phosphatidylcholine (lecithin), sphingomyelin, phosphatidylglycerol are components of lung surfactant that lowers alveolar surface tension. Immature lungs don't produce enough surfactant --> RDS, increasing risk of partial lung collapse. L/S ratio > 2:1 with phos...glycerol indicates mature lungs.
Cholesterol and gallstones?
Too much cholesterol in bile + too little bile salts = cholesterol hardens into pebble solids (stones). Treated with oral chenodeoxycholic acid to supplement bile acid pool and help dissolve stones.
How is protein charge determined?
Gel electrophoresis and serum proteins?
pH in relation to pKa of amino, carboxy, and R-groups. pKa > pH means takes H+ ion.
Gel electrophoresis used to resolve major serum proteins like albumin, alpha-1, 2, beta, and gamma globulins.
Disulfide bonds in hairstyling?
Keratin has high cysteine content and can be oxidized/reduced to curl/straighten hair.
Cytoplasm does not have proper oxidizing environment due to high  of glutathione antioxidant
How do enzymes affect reaction speed?
Does ∆Gº' indicate reaction velocity?
Act as catalyst to increase velocity
No, only if energy is needed or not (positive/negative sign)
Most important class of biochemical reactions?
Redox, since oxidation provides most energy for aerobic metabolism. Electrons used in ETC to pump protons and make ATP.
One major role of kidneys with blood?
Regulate blood pH
How do kidneys regulate blood pH?
Remove protons in form of ammonium ion (NH4+) and reabsorb bicarbonate (HCO3-). Low blood pH triggers increase in both of these processes.
What does the gastric proton pump do?
Pumps H+ into gastric lumen to make HCl with Cl- for gastric acid.
What to do to reduce gastric acid secretion? Why?
Inhibit gastric proton pump with omeprazole, etc. Used for ulcers, indigestion, heartburn.
What are side effects of omeprazole?
Decreased HCl in gastric acid causes decreased nutrient absorption (vitamin B12, calcium ions), increased food poisoning sensitivity, reduced efficacy of gastric enzymes (pepsin, gastric amylase, gastric lipase) that digest proteins, carbs, and lipids.
What is allopurinol? Targets what?
Pharmaceutical agent used to treat chronic gout (accumulation of uric acid in synovial fluids, thus joint pain/inflammation). Targets xanthine oxidase - enzyme that converts hypoxanthine to uric acid in purine degradation.
How is allopurinol a suicide inhibitor?
Binds active site of xanthine oxidase, which then converts the allopurinol to its actie metabolite oxypurinol, which binds tight and is slowly released (noncompetitive inhibitor).
What is myasthenia gravis?
Autoimmune disease caused by inhibition of acetylcholine signaling by antibodies that bind to acetylcholine. Muscle weakness, fatigue, can't hold one's gaze.
How can physostigmine treat myasthenia gravis?
Inhibits acetylcholinesterase enzyme via binding and subsequent inactivation. Acetylcholine can't be broken down in synaptic cleft.
How are metalloenzymes inhibited?
Chelating agents bind to and remove metal cofactors from enzyme. EDTA is one such chelating agent.
What are symptoms of lead poisoning?
Abdominal pain, anemia, irritability, headaches, impaired nervous system development and encephalopathy
How do chelating agents treat lead poisoning?
Ex. Ca-EDTA treatment causes lead (higher affinity for EDTA than calcium) to displace calcium and be removed to create Pb-EDTA and excreted in urine. In children, chelating agent succimer is used.
What is Tn-I? How is it related to myocardial infarction?
The inhibitory subunit of troponin (3 subunits total). After a myocardial infarction, one of the 3 isoforms (cTn-I)'s serum levels in the cardiac muscle are elevated. sTn-I is found in skeletal muscle.
What are 6 enzymes whose elevated blood  indicates a certain disease?
What is Fanconi-Bickel syndrome? Symptoms and treatment?
Inherited deficiency of GLUT2 glucose transporter in liver, pancreatic beta cells, and proximal renal tubules. Causes stunted growth, hepatomegaly, and bouts of hypoglycemia between meals but hyperglycemia after a meal. Glucose and galactose not rapidly cleared from circulation after eating. Glucose generated via gluconeogenesis not released. Treatment is small frequent meals and avoid galactose in diet.
How does GLUT2 aid in glucose sensing?
GLUT2 maintains intracellular and extracellular glucose levels ("sensor") in pancreatic beta cells. Increased blood glucose causes glucose to be brought into cells by GLUT2 and metabolized into ATP. Increased ATP causes K+ channels to close --> beta cell depolarization --> voltage-gated Ca2+ channels to open --> calcium influx --> insulin release. Calmodulin and calcium/calmodulin-dependent protein kinase (CamK) increased also for insulin synthesis.
What is a glucose tolerance test?
Test for type 2 diabetes. Oral glucose followed by fasting. Measure plasma glucose before and and at intervals after glucose administration. Resting should be <6.1 mmol/L. After 2 hours, <7.8. Levels >11.1 after 2 hours = diabetes diagnosis.
What is drug-induced lupus erythematosus?
Body metabolizes many drugs via acetylation. People with this have genetic mutations in acetylation reaction enzymes. Longer half-life of drugs = converted to toxic by-products --> antinuclear (antihistone) antibody production. Symptoms are like lupus (muscle/bone pain, rashes, inflammation of lungs and heart, fever, fatigue).
How much protein does a typical 70kg (154 lb) person consume, degrade, and synthesize daily?
100g consumed, 400g degraded and 400g synthesized
Component amino acids broken down to provide energy or create biomolecules. Nitrogen from AA's channeled into urea cycle of liver to be excreted as urea (urine) or sweat.
Carbohydrate general formula
Cn(H2O)n n = 3-9
Carbohydrate metabolism provides large part of the body's ___?
Four main common dietary carbs
Starch, sucrose, dietary fiber, lactose
What is starch?
Nutritional reservoir in plants, glucose polysaccharide
2 main forms of starch
amylose (unbranched) and amylopectin (branched)
What is sucrose composed of?
Disaccharide of glucose and fructose
Where is sucrose found?
Fruits and veggies
Dietary fiber is of ___ origin
What is lactose?
the major dietary carb of animal origin
What is lactose composed of?
Disaccharide of glucose and galactose
glucose, fructose, galactose, ribose
Maltose, lactose, sucrose
Oligosaccharides are composed of __ monosaccharides
Glycolipids and glycoproteins
Oligosaccharides are found where?
Attached to membrane lipids and proteins
Polysaccharides are composed of __ monosaccharides
Glycogen, starch, cellulose
3 ID parts of a monosaccharide
#C, functional group, stereoisomer form
Two functional groups of carbs?
Ketone and aldehyde
What are epimers?
Diastereomers that differ in only 1 chiral center configuration
what is an epimer?
diastereomer that differs in only one chiral center
What are monosaccharide epimers?
One OH group is switched to other side
What determines the D- or L- sugar stereoisomer forms?
Position of chiral -OH farthest from carbonyl
Most sugars are in __-series in humans
How to go from Fischer to Haworth projections?
Last chiral OH attacks anomeric carbon, all OH's on right go down, all OH's on left go up, CH2OH of C6 goes up. Anomeric OH goes up or down based on alpha or beta anomer
Alpha vs. beta anomer sugars
Alpha - anomeric OH grp opposite C6 grp (down) Beta - anomeric OH grp same side as C6 grp (up)
Pyranose vs furanose
Pyranose = 6 member ring Furanose = 5 member ring
Why does ring structure form?
Glucose Fischer projection
R, L, R, R
Fructose fischer projection
(C2 ketone) 3L, 4R, 5R
5 main metabolically important chemically-modified monosaccharides
Central C, hydrogen, amino group, R-group, carboxyl group
Most protein-forming AA's in body exist in the ___ form, except ___
Amino and carboxyl pKa's
Amino - 9.1-9.7 Carboxyl - 1.8-2.8
What are the 10 essential amino acids?
Ile, Leu, Met, Phe, Trp, Val, Thr, Arg, His, Lys
What are the 10 non-essential amino acids?
Ala, Gly, Pro, Asn, Cys, Gln, Ser, Tyr, Asp, Glu
Henderson Hasselbach equation
pH=pK + Log [base/acid]
The pH at which the AA charge is zero is the ___
Fuel supply, structural support (keratin, collagen), activity (enzymes, cell signalling)
AA's are linked in a polypeptide by ___ bonds
AA primary sequence is written _ to _ terminus
N to C
Protein secondary structures
Alpha helices, beta sheets, beta turns
Protein tertiary structure held together by which forces?
Hydrophobic interactions, disulfide bonds, metal ions, H-bonds
2 main tertiary structures
Fibrous or globular
Most abundant globular protein in blood is ___
Quaternary structure subunits held together by what?
H-bonds, salt bridges, hydrophobic interactions, Van der Waals forces
1g lipids yields _ kcal energy
1g protein or carb yields _ kcal energy
Free energy change equation for a reaction
∆G = ∆Gº' +RTln([B]/[A])
Equation for standard free energy change
To couple reactions, what is required?
Must share a common intermediate
Why can you calculate total ∆G for coupled reactions?
∆G's are additive
How to get reaction to flow?
Increase reactant or decrease product (Le Chatelier)
Is gibbs free energy indicative of the reaction velocity?
What is diabetic ketoacidosis?
Diabetics cannot burn glucose well, burn FA's instead, creating ketone bodies that release protons to lower pH
Two types of biochemical reactions
Redox and acid-base
what are the two types of biochemical reactions
oxidation reduction reactions and acid base reactions.
All biochemical reactions involve the ___ of electrons, atoms, or groups of atoms
Normal blood pH range
7.37 - 7.43
What is respiratory acidosis?
Blood pH <7.37 due to hypoventilation, i.e. CO2 build-up, so blood pH reaction shifts to make more protons
What is the equation for blood pH regulation?
H2O + CO2 <--> H2CO3 <--> H+ + HCO3-
Strong acid addition (lactate, ketone bodies) or bicarbonate loss (diarrhea, weak kidneys)
Blood pH >7.43 via hyperventilation, decreased CO2, equation shifts
pH > 7.43 via strong base addition (antacid ingestion) or acid loss (vomiting)
Another way to remember relationship between ventilation and proton gain/loss
Hyperventilation is like breathing out protons, while hypoventilation is maintaining protons
Main physiological acids
acetoacetic acid and beta-hydroxybutyric acid
Main physiological bases
bicarbonate and ammonia
pH = pKa + log(conj base/conj acid)
If more conj base than conj acid in blood, what happens to pH?
log(>1) is positive, means pH from H-H equation increases
Main metal ions required by metalloenzymes
Copper, iron, magnesium, selenium, zinc
Ex. protein that needs copper
Cytochrome c oxidase - accepts e's from cytochrome-c in ETC
Ex. protein that needs iron
Hemoglobin (heme group)
Ex. protein that needs magnesium)
ATPases (ATP -> ADP) and kinases (phosphate grp transfer)
Ex. protein that needs zinc
Superoxide dismutase (binds free radical O's)
Heme, NAD+, NADP+
Pepsin optimal pH and location
pH = 2, stomach acid
Trypsin optimal pH and location
pH = 8, duedenum/intestines
How does pancreas raise pH in intestines from that of stomach acid? Why?
Pancreatic juices contain bicarbonate to raise pH for trypsin optimal pH of 8
How is reaction rate related to temperature?
Fastest at optimal temp, slower below and above (heat-induced enzyme denaturation)
What is the catalytic triad?
Asp, His, Ser interaction in chymotrypsin where the H of the serine OH is taken by the Histidine ring, creating a potent alkoxide ion (O-) on the serine for the active site to cleave peptide bonds via hydrolysis
What does peptide hydrolysis by chymotrypsin have to do with covalent and acid-base catalysis?
Histidine acts as a general base catalyst by accepting the proton from serine, creating the alkoxide ion
What's the general formula for CHO
what are common dietary carbohydrates?
starch-- chained glucose amylose unbranced and amylopectin is branched. sucrose--fructose and glucose dietary fiber Lactose--glucose and galactose
Sxs of belly pain, gas, bloating after consuming dairy could be caused by deficiency of what enzyme? what does it do?
Lactase, hydrolyzes glucose and galactose
Glycogen Glycoproteins Maltose Fructose Examples of
what are the 3 components to identify a monosaccharide?
-Carbon number -Functional group -Stereoisomer form
what are the functional groups of sugars?
ketose and aldose
how are the D and L labelings assigned
to the chiral OH group farthest from the carbonyl group D-on the right L-on the left
what is the importance of D vs L sugars
most sugars are in the D series in humans and it is important because of the specificity of enzymes and receptors to specific D and L configurations.
where does a CHO spend more of its structural time?
as a ring--but a very small amount as a chain structure.
What can the body do with sugars?
use them as energy or use them metabolically as -Deoxyaldose (major part DNA) -Acetylated amino sugars (cell signaling, cel adhesion, immuno response -Sugar esters (nervous system -Sugar alcohols (food additives)
how are saccharides joined?
what is the difference in glycosidic lyncages between Amylopectin and Amylose?
Amylose is alpha 1-4 while Amylopectin has aplha 1-4 linkages but also branches using alpha 1-6 linkages.
what is the bonding pattern of cellulose and how/why does it differ in its structure from glycogen and starch
cellulose is B1-4 linked. Cellulose is very long and straight while starch and glycogen are bent as they need to more suitable for storage.
fatty acids are key components in glycolipids and phospholipids which are found where?
in cell membranes
what's the difference between saturated and unsaturated fatty acids and what makes one essential?
Saturated means no double bonds in the Carbon hydrogen chain. Some fatty acids are essential because humans cannot introduce a double bond beyond Carbon 9
what are isoprenoids and the three main examples of them?
5 carbon molecules that make up -bile salts -hormones -cholestrol
What is Km and how does it relate to reaction velocity?
Equation in relation to substrate concentration?
Constant [substrate] where v = 1/2 v-max
V = (Vmax[S])/Km + [S])
What does the M-M kinetics graph look like?
Hyperbolic with flat top at v-max and Km at 1/2 v-max
Km is __ proportional to velocity
How do the Km's of glucose transporters in the brain and pancreas differ? Why?
Brain - low Km for constant glucose feed because always needs to be active (Km = 0.1)
Pancreas - high Km for activity only when glucose levels are high after a meal
What are the effects of competitive inhibition on Vmax and Km? Why?
What does the graph look like then?
Vmax is unchanged, while Km is increased. Increasing [S] allows substrate to out-compete inhibitor.
The hyperbolic curve is less steep but plateaus at same vmax.
amino acids serve as precursors to what?
Acetyl CoA--from pyruvate which is from amino acids (gluconeogenisis) -precursors to heme, biogenic amines, etc. -homones i.e. insulin and glucagon
what happens if you are missing an essential amino acid in your diet?
you have a negative nitrogen balance and begin to have Sxs of deficiency
What are the effects of noncompetitive inhibition on Vmax and Km? Why?
What does the graph look like then?
Vmax lowered, Km unchanged. Increasing [S] will not allow substrate to out-compete inhibitor.
Same steepness with equal Km's, but plateaus at lower vmax.
What are the effects of uncompetitive inhibition on Vmax and Km?
Both lowered since inhibitor only binds to enzyme-substrate complex. Look up why...
what are amino acids made up of? also mention the pH of any dissociable protons.
Central carbon amine group--pKa 9.1-9.7 carboxylic acid--pH 1.8-2.8 R-group
Effects of enzyme inactivation on Vmax and Km? Why?
Vmax lowered, Km unchanged. Increasing [S] won't allow substrate to out-compete inhibitor.
how does enzyme inactivation effect the vmax and km?
binds to the active site and lowers vmax but leaves km unchanged.
What kind of V/[S] kinetics curve do allosteric enzymes create?
Sigmoidal rather than hyperbolic
How do allosteric activators and inhibitors affect the v/[S] kinetics curve?
Activator - shifts curve left
Inhibitor - shifts curve right
What is one allosteric activator that stimulates gluconeogenesis? Where does it come from? How does it relate to my low-carb diet?
Acetyl-CoA, which comes from fatty acid breakdown. So must break down fats to build sugar for energy. If sugar creation is needed (i.e. not consumed), we will break down fats to get the necessary effector molecule.
What are isozymes and how do they relate to diagnosing diseases?
Isozyme - enzymes w/ diff. AA sequence but catalyze same reaction.
Enzymes/proteins have different isozymes that are present in different tissues. If seen in blood, sign of breakdown of that tissue.
What 2 types of proteins help new proteins fold correctly?
Chaperons and enzymes
What 3 things help localize and degrade proteins as necessary?
Translocation machinery, proteasomes, and autophagic activities
What are unfolded proteins bound to other unfolded proteins called?
what are the polar amino acids? and where are they found?
in the cytosol, and extracellular environment uncharged +Threonine, Tyrosine, Serine, glutamine, cystein, asparagine, Negatively charged, Aspartic Acid, glutamic acid Positively charged, Arginine, Histidine, Lysine
What receptor complexes in mitochondrial membranes recognize preproteins to be brought in and folded?
Tom40 pore (Tom complex) in outer membrane (recognized by Tom20 and Tom22), and Tim23 complex in inner membrane
what is the pI?
pH where the charge is 0
How is homeostasis regulated at a transcriptional level?
via transcription factors that can promote or repress gene transcription
Post-translational protein modifications are crucial to a proteins what? (5)
Function, regulation, subcellular localization, interaction w/ other molecules, and degradation
Where does post-transcriptional protein modification take place?
on specific sites of certain amino acid residues
derivatives of AA
5 main post-translational protein modifications
Acylation (acyl group attachment) Glycation (nonenzymatic glucose attachment) Glycosylation (enzymatic sugar attachment) Phosphorylation (phosphate group via ester bond) Ubiquitination (small protein called ubiquitin)
why are proteins important?
Fuel supply i.e. TCA cyle Structural support i.e. elastin, karatin, collagen activity i.e. enzymes, cell signaling, motion
What does ubiquitin mark?
Mark for degradation
2 forms of intracellular protein degradation
Lysosome (engulfed and eaten by enzymes)
Proteasome (fed through subunits and chopped up)
Extracellular protein digestion?
Extracellular proteolytic enzymes secreted as inactive zymogens
Intestinal example of extracellular proteolytic enzyme?
Trypsinogen cleaved into trypsin by enteropeptidase. Then Trypsin can cleave other trypsinogens independently of enteropeptidase.
discuss primary structure vs secondary structure vs tertiary structure vs quaterinary structure.
P-linearly written linked by peptide bonds. S-coil, pleat, and turn from hydrogen bonding T-3D configuration from hydrophobic interactions, S-S bonds, metal ions and H bonding Q-subunits arranged into complexes. H bonded, salt bridges, hydrophobic interactions, van der waals forces.
How do membranes assist with homeostasis?
Controlling substance entry and exit, enclosing toxic material, and allowing food, water, waste exchange
what's the difference between fibrous proteins and globular proteins?
F- Parallel single linear axis poly peptides. form tough water insouble fibers G- Tightly foleded ~spherical
One catabolic mechanism of dysfunctional cellular component degradation and recycling?
Autophagy, where autophagosome engulfs old component, then lysosome fuses with autophagosome to create autolysosome and break down component
what is the most abundant glubular protein
Mitochondrial matrix is the site of what 4 things?
Beta-oxidation of fatty acids, TCA cycle, urea cycle, and calcium ion storage
3 ways mitochondria maintains homeostasis
Fusion of healthy with unhealthy to mitigate stress via complementation
Fission into 2 to remove damaged portion w/o losing the mitochondria (or to create a new mitochondria)
Complete elimination via mitophagy
A<-->B in the free energy equation G=Gnot +RT Ln([B]/[A]) describe what you can do to alter the the delta G
you can decrease [B] or increase [A]
if your delta G is not a very big negative how can you speed up the reaction and make it more favorable.
add energy e.g. ATP
how do enzymes effect a reaction?
they increase the speed by lowering the activation energy.
what is the normal blood pH?
Hyperventilation causes respiratory...
hypoventilation causes respiratory..
diarrhea, and weakened kidney function causes loss of what and metabolic...
loss of bicarbonate metabloic acidosis
vomiting causes loss of what and metabolic...
loss of protons and metabolic alkalosis.
what are the physiological acids from type II Diabetes?
Acetoacetic Acid, and Beta hydroxybutyric acid.
what are two physiologic bases?
what is pH equal to?
why is Cu important
necessary for enzymes in the Mitochondria and for cytoprotection.
what is Mg associated with?
phosphates and kinases and ATPases
where do we get iron?
who would likely be iron deficient?
women in childbearing age range and vegitarians
where are Se and Zn found in the diet
Se in corn Zn in meat
where does the enzyme do it's work?
what is the optimal pH for pepsin? and typsn?
2 and 8 respectively.
what are the three residues of chymotrypsin? aka catalytic triad
Asp, His (gets protonated from Ser), Ser (gets deprotonated)
what is the km?
concentration of the subsrate at which you get half of the vmax *analogous to its efficiency
the glucose transporter of the brain has a km which is high or low?
competitive inhibition vmax and km ex ethanol dehydrogenase methanol and ethanol
vmax uneffective km increased
discuss how noncompetitive inhibition effects vmax and km
vmax is lowered because you effectively reduce active enzyme concentration. km unchanged.
how does uncompetitive work and effect vmax?
binds to enzyme substrate complex and inhibits the target enzyme. lowered both vmax and km
what is an allosteric enzyme?
bind to sites other than the active site and alter the active site.
how does acetyl CoA effect glycolysis?
it increases pyruvate carboxylase which increases the TCA cycle intermediates which helps metabolize fats.
what are isozymes
proteins that resemble each other but their sequence is slightly different.
LDH is an isozymes with 4 tetramers s how many isoenzymes are there?
5 H and M's
what isozyme of LDH is typically found in syrum?
what increases the rate of the reaction? what ultimately determines if a rxn occurs?
enzymes delta G
how do the kidney's control acid and base?
controlling bicarbonate reabsorption and increasing NH4+ (can't get back in because it's charged)
how do proton pump inhibitors effect the pH of the stomach and digestive enzymes?
increase the pH which decreases the effectiveness of digestive enzymes.
what enzyme could be useful to detect serial MI's
what is homeostasis
maintenance of metabolic equilibrium within an organism by a tendency to correct for changes.
how is glucose taken up to the cell in order to maintain homeostasis?
brought in through the GLUT 4 transporter after insulin binds and signals microvesicles carrying the transporters to fuse with the cell membrane
how many glucose transporters are there? How many are the very important ones to homeostasis?
14 GLUT1-4 are important and tissue specific.
where are GLUT1,2,3 and 4 transporters found?
GLUT1-most cells except epithelialcells of kidney and small intestine, hepatocyltes GLUT2- pancreatic B cells =glut one GLUT3-Brain, placenta ad testes+glut1 GLUT4-Adipocytes, cardiac and skeletal muscle +glut1
where does anerobic glycolysis occur?
where does aerobic glycolyss occur?
in the cytosol
what happens when blood glucose is low and glycogen stores are depleted?
Gluconeogenisis from pyruvate
How is protein homeostasis achieved?
through proper expression, folding, transport and clearance of proteins
if you look under a microscope and identify several plaques for a decreased patient. what could be the cause?
the chaperones were absent or not working
how do translocator proteins like Tom Complex transport proteins?
they recognize the presequence and bring it through the membrane
how do transcription factors effect protein homeostasis?
they dictate which genes are transcribed _promote or supress protein synthesis.
what are post translational modifications and why are they important?
they appear after the proteins are being brought to the Golgi -tagged telling where they are to be shuttld -need to be modified to work -tagged to be destroyed i.e. ubiquinated
why is Hb1Ac measured?
measurement of the glycosylation Hb. If too high then indicator that there is a persistently high blood glucose level and possible Diabetes.
what is ubiquination and why is it important?
attachment of a ubiquitin, and tags protein to be degraded
what is acylation and why is it important?
attachment of acyl group. acylation of small G proteins with palmitic acid or myristic acid affects their attachment to sbcellular membranes.
what is phosphorylation and why is it important?
addition of a phosphate group. Can activate or inhibit protein function.
how is protein degradation controlled intracellularly?
Lysosomal degradation, and proteasomal degradation
how does proteasomal degradation work?
Ubiquitin binds to protein that is to be degraded. Proteosome brings in the ubiquitineated protein, chops off the ubiquidine and then degrades the protein to amino acids
how does lysosomal degradation work?
lysosomes contain a concentrated proteosomes concentrated and isolated.
in ALS there is an aggregation of plaque proteins. why could this occur with respect to proteolysis?
the lysosomes and/or the proteasomes are not working or are working very slowly.
how are proteins controlled extracellularly?
Enzymes exist in zymogen form and then are activated in the proper place.
what is a zymogen? and what is the suffice for zymogens?
an inactive precursor version of the protein --ogen
how is trypsinogen activated?
first by enteropeptidase and then by itself.
how do cell membranes maintain homeostasis?
-Control what comes in the cell -encloses toxic material -allow for exchange of food, water, waste across the barrier. -carry carbohydrate chains that recognize other proteins.
what is autophagy?
as the cells are being basic catabolic mechanism that involves cell degradation of dysfunctional cellular components.
how does autophagocytosis work?
the dysfunctional cellular components are isolated by and isolation membrane. The Autophagosome then empties its contensts in the lysosome where the lysosome chops up toxicities.
what happens at the mitochondria?
B-oxidation of fatty acids, -TCA cycle under O2 conditions -Urea cycle -storage of Ca++
how do mitochondria maintain homeostasis?
fission and fusion
what is Mitochondrial Fusion?
two mitochondria come together and mix the contents of the partially damaged mitochondria as a form of implementation. degrades the misfolded or damaged proteins.
what is mitochondrial fission?
The creation of a new mitochondria by splitting and pinching all of the misfolded proteins off into one of the mitochondria. eliminate the old mitochondria through lysosomes.
Membrane phospholipids are ___, meaning both polar and nonpolar
Which biomolecule groups are found embedded in the membrane lipid bilayer?
Lipids and proteins
How are carbohydrates connected to the lipid bilayer?
Covalently attached to membrane lipids and proteins
Membrane lipids and proteins are frequently ___ on the extracellular side of the bilayer
glycosylated with carbohydrate molecules
Two main types of phospholipids?
What's the difference?
Glycerophospholipids - glycerol backbone w/ phosphate + 2 FA's + unique head group on phosphate
Sphingolipids - sphingosine backbone (1 hydrocarbon chain in place of where FA would be)
How to name a glycerophospholipid with a specific head group?
What are the components of sphingomyelin?
Sphingosine backbone w/ 18C FA, phosphate, and choline head group
What is the most common sphingolipid in the membrane outer leaflet?
3 types of membrane lipids
Phospholipids, glycolipids, cholesterol
How is cholesterol imbedded in the membrane?
Its hydroxyl group on the steroid (ringed) portion interacts with FA hydrophobic tails
Na - out K - in Cl - out Ca - out Mg - in HCO3 - out Phosphate - in H+ - EVEN
Which extreme ion gradient is very important in neurotransmission?
Calcium ions - 10,000x more outside cells
What kinds of molecules can undergo simple diffusion?
Small, non-polar, uncharged
What kinds of molecules undergo facilitated diffusion? What kinds of proteins help with this?
Large and charged
Channels or transporters
How do channels move polar molecules?
Have core of polar residues on inside
How to passive transporters work?
Binding of molecule causes conformational change to release molecule on other side
Sub-kinds of transporters
Uniporter - 1 substance 1 direction
Cotransporter - 2 substances - Symporter - same direction - Antiporter - oppposite directions
What is Cystinuria and how does it relate to transporters?
Defect in transport system for uptake of dimeric cystine (2x cysteine) and dibasic arginine, lysine, and ornithine AA's
Leads to cystine crystals/stones in kidneys (renal calculi)
What is Hartnup disease and how does it relate to transporters?
Defect in transporter for non-polar or neutral AA's in kidneys and intestine
What are common ligand categories for ligand-gated ion channels?
Neurotransmitters and hormones
What creates the normal voltage gap across the membrane?
Lots of negative charge inside cell via chloride inside and calcium outside
What triggers voltage-gated ion channels?
Depolarization of membrane potential via influx of + charge inside cell
Where are VGIC's and LGIC's found in neurons?
VGIC - presynaptic (calcium rushes in)
LGIC - postsynaptic (ligand = newly released neurotransmitters)
How does primary active transport work? Examples?
Uses ATP hydrolysis to fuel movement against gradient through transporters
Ex. Na/K-ATPase, Ca-ATPase
How is 2º active transport different than 1º? Examples
Uses energy from other molecule moving down its gradient to move something else up its gradient. This gradient is maintained via 1º active transport
Na-Glc transporter, Na/Ca exchanger
What is SGLT1?
Sodium-glucose transporter that mediates unidirectional movement of sodium (down gradient) and glucose (up gradient) across SI and renal tubules
Useful for grabbing all possible glucose out of the intestinal lumen for storage for later energy use
What is the NCX? Function?
Sodium-calcium exchanger, which imports 3 sodium along gradient while exporting 1 calcium against gradient.
Keeps intracellular calcium low
2 routes of sugar transport into blood from lumen using:
active transport, facilitated diffusion
1. SGLT1 move Glc/Gal along Na gradient via 2º active transport 2. Facilitated diffusion across enterocyte into blood via GLUT2
1. Fructose moved by facilitated diffusion down gradient via GLUT5 (apical side) and GLUT2 (basal side) in/out of enterocyte
What are cardiotonic drugs and how do they work in regards to ion transport?
Inhibit Na/K-ATPase on cardiac myocytes, causing intracellular Na buildup, thus Ca buildup due to slower NCX. Ca buildup means stronger heart contractions with each action potential
How do defective transporters lead to cystic fibrosis?
Mutated CFTR gene causes defective active transport chloride channel from inside to outside of cell despite ATP energy use. Cl and salt buildup in cells causes water to move into cells, thus thick mucus outside cells in lungs
Why is rough ER called rough?
Studded with ribosomes
What are folds in the ER called?
Functions of rough ER
protein modification and assembly, protein segregation for intracellular or extracellular use
What are polysomes? Where can they be found?
Groups of ribosomes (poly[ribo]somes) along single mRNA
How do most proteins exit the RER?
Via vesicles pinched from the RER membrane to be transported to the cis-Golgi
Cis - entry face (towards ER) Trans - exit face (towards cell membrane)
Functions of Golgi apparatus
Modify carbs on glycoproteins and proteoglycans, synthesize sugar polypeptides, synthesize sphingomyelin and glycosphingolipids, marking lysosomal enzymes, packaging and storing secretory products in vesicles/granules
What is anterograde vs. retrograde traffic from golgi?
Antero - sorting cargo to secretory or lysosomal pathways
Retro - sorting back to ER
Two types of vesicle coatings (where are they used)
Clathrin - Golgi to lysosomes or endocytosis (cell membrane) to lysosomes
Coat protein (COP) - between golgi cisternae (COP1) and from ER to golgi (COP2)
How do vesicles bind cargo and pinch off from membrane?
Adaptins mediate clathrin-receptor attachment, while Dynamin surrounds neck of pinch to release new vesicle
Primary vs secondary lysosomes
1º - new, inactive 2º - active
Function of lysosomes?
Break down anything it's given
2 main steps of lysosomal sorting pathway in Golgi
1. Enzymes phosphorylated by mannose-6-phosphate (M6P)
2. M6P-bound enzymes bind to M6P receptor on Golgi inner surface, then break off to create a lysosome (clathrin coat is released as well as the M6P receptor)
How do lysosomes maintain an acidic environment?
They have an ATP-dependent proton pump to pump protons in against gradient
What type of enzymes are most lysosomal enzymes?
What's a residual body? What does the cell do with them?
3º lysosome containing leftover product after digestion
Either secrete them by exocytosis or become lipofuscin granules that remain in cytosol
3 pathways for intracellular degradation
Phagocytosis (of bad external body), autophagy (of damaged organelle), and receptor-mediated endocytosis (of specific macromolecules from outside cell)
What are endosomes and how do they relate to lysosome (2º) formation
Vesicle carrying contents from endocytosis
Fuse with 1º lysosome from golgi to release hydrolases on contents and create active 2º lysosome (once cell membrane receptors and M6P receptors have been recycled out of "late endosome")
What is familial hypercholesterolemia? (3 levels)
Elevated LDL in blood due to mutated LDL receptor gene
LDL receptor can't bind LDL
LDL receptor binding reduced
LDL receptors incapable of bringing cholesterol into cell after binding (internalization)
How does autophagy protect against diseases like cancer?
Protects against genome instability and prevents necrosis
How does phagocytosis work?
Engulf microbe or pathogen from external into a phagosome, bind with lysosome, digest, release residual material waste
What is Tay-Sachs disease?
One of many diseases involved with mutated lysosome enzymes. A mutated lysosome enzyme causes GM2 gangliosides to build up in lysosomes, causing early cell death.
What are peroxisomes?
Contain enzymes that form H2O2 when breaking down (beta-oxidizing) FA chains. The hydrogen peroxide is then broken down by catalase into oxygen and water. Also synthesize bile acid and cholesterol, and detox alcohol.
What are Zellweger spectrum disorders?
Peroxisome biogenesis disorders caused by defects in assembly
Which organelle makes acetyl CoA?
Mitochondria, during TCA cycle
Mitochondrial diseases are caused by what 2 things?
Mutated mtDNA, and mutated nuclear DNA for imported proteins
Why can there be a wide spectrum for how mitochondrial diseases are passed on?
Only some mitochondria from mom are chosen for each egg. If most are mutated, child will be severely afflicted, etc.
What are cytoplasmic inclusions?
temporary build-up of structures, food stores, pigments, etc. in cytoplasm to be used by cell (glycogen, lipids, melanin, lipofuscin)
what are the functions of the TCA cycle and where do they take place?
-oxidizing Carbon (pyruvate) to produce high energy electrons -amphibolic (catabolic and anabolic) e.g. amino acids -bioprecursor syntheseis --in Mitochondria.
4 basic tissue types
Epithelia, connective, muscle, nerve
Functions of connective tissue
Protect/support body and organs, bind organs together, reserve fat energy, immunity
List all things covered in epithelia
Body surface, organs, body cavities, ducts
Which germ layer does epithelia develop from?
Main type of epithelium on skin surface?
Epithelium that lines serous body cavities? Grossly called what?
Epithelium that lines blood and lymph vessels?
What is metaplasia?
The ability of epithelial cells to convert from one type to another based on chronic environment changes
Epithelia have little ___ material (i.e. closely packed)
what is the energy density of glucose vs. fats? How many molecules of ATP do you get from one glucose vs 1 palmatic acid
Surface of epithelium exposed to lumen or exterior
Basal surface of epithelium is attached to a ____
Cells exhibit apical, lateral, and basal ___ that are structural and functional (i.e. they are ___)
Main functions of apical specializations?
Movement, secretion, absorption
Main types of apical specializations
Cilia, microvilli, stereocilia
Describe features of cilia
Motile, long, coordinated movement of material, extensions of cytoskeleton, contain core of microtubules (axoneme) in 9+2 arrangement, anchored to basal bodies, movement generates current
Explain the 9+2 arrangement in cilia?
Core of microtubules consisting of 9 pairs around outside plus 1 pair in middle
How are cilia rooted in place?
Connected to basal body that is rooted via rootlets
What are the anterograde and retrograde features of cilia?
They can move things up or down the cilia
What is the basal body of cilia made of?
9 microtubule triplets in a circle
How do cilia move?
Microtubule doublets connected via nexin linking protein. Dynein arms extend from doublets and work in ratchet mechanism using ATP to move.
What is primary ciliary dyskinesia? Other names?
Genetic defect --> uncoordinated or absent cilia, leading to cell layers not moving correctly in embryogenesis. Organs abnormally placed (situs inversus). Also severe chest infections via lack of mucus removal, and infertility.
Explain zonula adherens, including important proteins
Adhering junctions, beneath tight junctions, contain plaques on each cell membrane connected by cadherins and the afadin-nectin complex. Web of actin microfilaments inside cells. Plaques keep cells farther apart than in tight junctions.
What amino acids are capable of being broken down to gluconeugenic precursors and acetyl CoA?
what amino acids can only be metabolized to Acetyl CoA?
what is the sole building block for Isoprenoids and fatty acids?
Explain macula adherens, including important proteins
Desmosomes - below adhering junctions, link with cell cytoskeleton for strength. Cadherins span the space like in Z.A., but the inner anchoring filaments are keratin, NOT actin
Explain gap junctions, including important protein
Communication junctions made of hollow cylindrical structures with hydrophilic cores called connexons that span the plasma membranes, made of 6 rod subunits of connexin arranged in a circle. Allow for rapid spread of information between cells via ion transport (calcium, etc.)
Differentiate the makeup of the basement membrane
Made up of basal lamina and reticular lamina (connective tissue). Basal lamina made of lamina lucida (multiple proteins) and lamina densa (type 4 collagen).
Usually, what does the basement membrane appear like in light microscopy?
Dark line below cell layer
Function of basal lamina?
Molecular filter, support, and cell migration during wound repair
Contents of sub-sections of basal lamina? Of reticular lamina?
Lamina lucida - extracellular glycoproteins
Lamina densa - type 4 collagen
Reticular lamina - collagen 1 and 3
in a starving state (DM or severe fasting) how are fats used as energy?
Beta-oxidized to Acetyl CoA. Cant go through CTA cycle becuase oxaloacetate is being used for gluconeogensis. LIVER CONVERTS TO keytone bodies to be used in brain and muscles.
What are hemidesmosomes? Contents?
Like half of a desmosome, but a special portion of cell basal domain to assist in anchoring to basal lamina. Made up of keratin filaments in cell, plate, plaque within plasma membrane, and anchoring filaments to basal lamina
BOLD = different than desmosome
how are ___ converted into Acetyl CoA? CHO Proteins Lipids
CHO--Glucose converted to 2 pyruvate to Acetyl CoA Proetins--Break down then converted to Acetyl CoA Lipids--broken down to fatty acids who are beta oxidized to Acetyl CoA
where is the high energy bond in Acetyl CoA?
in the Thioester bond at 7.5kcal/mol
under aerobic conditions, what happens to pyruvate after it is created from glycolysis?
travels through the mitochondrial membrane with the aid of the Mitocondrial Pyruvate Carrier. Then Pyruvate Dehydrogenase complex conversts it to Acetyl CoA and creats CO2 and NADH.
what are the Carbon components to the TCA cycle?
Ocaloacetate+Acetyl CoA-->Citrate-->Isocitrate-->AlphaKetoglutarate-->SuccinylCoA-->Succinate-->Fumarate-->Malate. Can I Keep Selling Sex For Money Officer?
what are the regulated steps/enzymes in TCA cycle and what does it mean to be regulated?
1,Citrate Synthase, 3 Isocitrate Dehydrogenase, 4 alpha-ketoglutarate Dehydrogenase It means they are irreversible.
what happens to pyruvate if there is a deficiency in Pyruvate Dehydrogenase phosphatase?
1- The Phosphate dehydrogenase complex is never dephophorelated and therefore it remains inactive and will not convert the pyruvate to Acetyl CoA. this results in lactic acidosis effecting the brain.
what can you do for someone who has pyruvate dehydrogenase complex defficeincy particularly in E1 subunit?
administer Vitamin B1 (cofactor), lipoic acid (stimulate PDC), abnd Biotin (helps metabolzie pyruvate differently). Also ketogenic Diet (not glucose).
What is the general function of the TCA cycle?
Degrade energy nutrients (oxidizing carbon fuels) to harvest high energy electrons. Also create biosynthesis precursors
What are macromolecule subunits broken down into?
Acetyl CoA - the entry into the TCA cycle
What is the creation goal of the TCA cycle?
Energy equivalent substances like NADH, FADH2, and GTP
Where does the energy from the TCA cycle go?
To be used in oxidative phosphorylation in mitochondria for ATP production
How do carbs become acetyl CoA?
Through glycolysis, followed by the conversion of pyruvate to acetyl-CoA by pyruvate dehydrogenase complex (PDC)
How do lipids become acetyl-CoA?
Through beta-oxidation of fatty acids
Which amino acids must be converted into acetyl coA?
The essential amino acids
How does Arsenite poison Human's?
It modifies/inhibits the E2 subunit (Lipoic Acid) of PDC. Also effects a-ketoglutarate dehydrogenase (has lipoic acid).
List the steps in the conversion of ethanol to acetyl-CoA? (intermediates)
Ethanol --> acetaldehyde --> acetic acid --> acetyl-CoA (--> CO2 and water)
What is the name of the conversion process from pyruvate to acetyl-CoA?
what regulates PDC in low energy states and high energy states?
LES--ADP, NAD+, Pyruvate, CoA
HES--ATP, NADH, Citrate, Acetyl CoA
Where is the chemical energy in the acetyl-CoA molecule?
In the thioester bond between the S atom and CoA (between acetyl group and coenzyme A)
How much energy at standard conditions does a mole of acetyl-CoA contain?
(∆Gº' = -7.5 kcal/mol)
The TCA cycle links what two processes?
Aerobic glycolysis and oxidative phosphorylation
How does a build of citrate in a high energy state effect energy prodction?
inhibits PFK (rate limiting in glycolysis) promotes Acetyl CoA carboxylase (converst Acetyl Coa to Manitol CoA which in rate limiting/first step of lipid sythesis [storage of energy]
What is given off in the decarboxylation of pyruvate to make acetyl-CoA?
NADH and CO2
Describe the first 4 steps of the TCA cycle with enzymes
Which steps of the TCA cycle of regulated? What does that mean?
1, 3, and 4
How does phosphatase contribute to the TCA cycle?
Dephosphorylates pyruvate dehydrogenase complex to activate it
what is another pathway for succinal CoA if it does not continue the TCA cycle?
can combine with glycine through the use of ALA sythetase and B6 to create Gama ALA (rate limiting step in heme production.
What happens to the TCA cycle if there is a phosphatase deficiency? Result?
Shuts down - PDC is always inactive, so pyruvate (from glucose) gets converted to lactate rather than acetyl-CoA
Results in lactic acidosis
What are the total products of the TCA cycle?
2 CO2, 3 NADH, 1 FADH2, 1 GTP
How does Fleuroacetate effect the TCA cycle?
Fleuroacetate combines with CoA to form Flueroacetyl CoA which competes with oxaloacetate to produce fluoricitrate which inhibits aconitase. This also inhibits PFK.
what are anaplerotic Rxns? examples?
Rxns that replenish the TCA cycle. e.g. degradation of amino acids to replenish Succinyl CoA, a-ketoglutarate, Oxaloacetate and Fumarate, carboxylation of pyruvate to form oxaloacetate.
What is the total reaction that PDC oversees?
Pyruvate + NAD+ + CoA --> Acetyl-CoA + CO2 + NADH + H+
what happens to people with pyruvate carboxylase deficiency? present in who?
excess pyruvate converted to lactatic acid which causes Sxs of seizures, muscle weakness, ataxia. Prevelant in Algonkian Indian tribaes
How is the TCA cycle amphibolic?
Catabolism - acetyl-CoA to CO2
Anabolism - cycle intermediates are precursors for biomolecules
Describe how the TCA cycle is anabolic.
oxaloacetate reduced to malate, transported back from mitochondrial matrix to cytoplasm to oxaloacetate, converted to Phospheonolpyruvate and ultimately Glucose synthesis*** (Gluconeogenesis). citrate can also be taken out to the cytoplasm, cleaved to form acetyl CoA and used for ***lipid sythesis. Amino acids can be formed from oxaloacetate and alphaketoglutarate.
Explain how PDC is regulated
Pyruvate dehydrogenase phosphatase (PDP) vs. kinase (PDK)
If PDP is active (not blocked), PDC is active. If PDK is active (not blocked), PDC is inactive (phosphorylated).
Excess amounts of calcium and magnesium activate PDP, while excess amounts of acetyl-CoA, NADH, and ATP activate PDK. Pyruvate, CoA, NAD+, and ADP block PDK (activate PDP)
how does the malate-aspartate shuttle work? and why is it needed?
Needed becuase NADH cannot pass through the mitochondrial membrane. Therefore NADH transfers electrons to enzyme that converts oxaloacetate to Malate. Malate comes through outer membrane and is antiported with alphaketoglutarate to the inner mitochondria matrix. Malate gets converted back to to oxaloacetate and NADH is regenerated inside the cell which drops it e's off at complex I of the Electron transport chain. *Aspartate is used to convert oxaloacetate to a-ketoglut and back
where is the malate aspartate shuttle primarily used?
heart, liver and kidney's
Why is the TCA cycle anaplerotic? Examples?
Many TCA intermediates are intermediates in biomolecule anabolism pathways
Ex. Degradation of amino acids to form many of the TCA intermediates
Ex. Carboxylation of pyruvate to replenish oxaloacetate
what is the glycerophosphate shuttle?
glyceroph 3 phosphate transfers NADH electrons from glycolysis throuhg the outer membrane into the inner membrane and gets converted to DHAP and gives the high energy electrons to FAD which introduces the e's to ETC at Coenzyme Q.
Which TCA cycle intermediates are part of glucose synthesis?
What happens when enough glucose is made?
Oxaloacetate converts to phosphoenolpyruvate (PEP) to glucose
Insulin is released and blocks pyruvate carboxylase (PC) from converting pyruvate to oxaloacetate
Which TCA cycle intermediates are part of lipid synthesis?
Citrate retroconverts to acetyl-CoA to create fatty acids and isoprenoids
where is the glycerophosphate shuttle primary found?
in skeletal muscle and brain tissue.
What TCA intermediates are involved in amino acid synthesis?
Oxaloacetate and alpha-ketoglutarate are both converted to different AA's with only minor changes
What are organ specific shuttles?
Different organs have specific systems for transporting metabolic needs into the organ
What are the two shuttle systems to get electrons from NADH through the mitochondrial membrane?
1. Malate-aspartate shuttle
2. Gylcerophosphate shuttle
Describe the malate-aspartate shuttle system
NADH gives electrons to oxaloacetate, converting to malate, which passes through mitochondrial membranes via porin and alpha-KG antiporter. Malate then hands electrons back to an NAD+ to be sent to ETC. Aspartate functions to be converted to and from glutamate to fuel the malate pool.
Describe the glycerophosphate shuttle system
NADH gives electrons to DHAP, converting it to G3P, which passes through 1st membrane, then gives electrons to FAD+ to convert to FADH2 for ETC
Where is each shuttle system used? Where do the electrons enter the ETC in each?
Glycerophosphate shuttle - skeletal muscle, brain - FADH2 to CoQ
Describe the structure of Heme.
4 Nitrogen containing Rings with carbon bridges. Fe at the center in the Ferrous State
where does the first part of of Heme synthesis take place? What occurs in this stage? What are inhibits to this Rate limiting Rxn
Takes place in the cytosol. Glycine and Succynil CoA combine with the help of Aminolevulinic Synthase to produce Aminoleuvulinic Acid. Vitamin B6 is used as a cofactor. Elevated Heme inhibits ALA Synthase. Fe promoted mRNA synthesis.
Where does Phase two take place? What is the first step? Second Step?
Mitochondria. Two ALA come together with the help of ALA Dehydrogenase to form Porphobilinogen (a 5 membered ring building block). Then porhobilinogen deaminase brings together 4 prophobilinogen building blockers together in a linear fashion
What enzyme introduces Fe+ into the center of Protophorphyrin?
what are porphyrias? What are the subtypes and main Sxs?
defects in synthesis of heme. Hepatic porphyrias.--neurologic Sxs Erythropoetic porphyrias.--skin photo sensitivity.
Acute intermittent porphyria--Hepatic has Sxs of what? and effects what enzyme?
Porphibilinogen Deaminase--first step in Phase Two. Sxs of deficiency of this porphyria leads to abdominal pain, and neurological Sxs.
Verigate porphyria--Hepatic effects what enzyme and has what Sxs?
Effects Protophorphyrinogen oxidase.--first step in phase III Sxs of this porphyria lead to photosensitivity and neurologic Sxs and Developmental delay in children. Of note: King George the III had this.
Erythropoietic Protoporphyria effects what enzyme and what Sxs?
Ferrotochelatase and effects photo sensitivity and gallstones--erythropoietic.
H20 Insoluble, taken by albumins to liver. There it gets conjugated with UDP-Glucuronate 2x by glucuronyltransferase.
what is the difference between indirect bilirubin and direct bilirubin?
Direct--is conjuncated with UDP gluconate Indirect is unconjucated.
After Conjugated bilirubin (with UDP--gluonerate) is released from the liver where does it go/what happens?
released into bile-->stomach where bacteria covert to urobilinogen Then: -Some reabsorbed and oxidized in kidney's to urobilin (yellow in pee) -Rest metabolized by colonic bacteria to Stercobilin (red-brown)
what type of Jaundice has Signs of -Elevated blood levels of unconjugated bili. -Normal blood levels of conjugated bili. -Normal ALT and AST -Urobilinogen present in normal urine levels -Bilirubin absent in the urine What can cause it?
Pre-hepatic Jaundice (no excess conjugated bilirubin to be excreated and conjugated bilirubin is not excreted in urine). Hemolytic Anemia, Neonatal Jaundice (Pre-me fetal hemoglobin hemolysis), Spurr Cell anemia.
what causes Jaundice with These Sxs? -Variable increases in conjugated and unconjugated bilirubin -Increase in Serum ALT and AST -Conjugated BR detected in urine.
What causes it?
Intrahepatic Jaundice --Cirrhosis and viral hepatitis. --Crigler Najjar Syndrome
what type of jaundice? --Elevated blood levels of conjugated bilirubin, small increase in unconjugated form -normal AST and ALT -Elevated canalicular enzyme ALP --Dark colored urine with a pale stool. --No urobilinogen in urine
Obstruction of biliary duct -Gall stones -Infiltrative liver disease -Drugs i.e. anabolic hormones, chlorpromazine phenytoin
A new born baby presents with jaundice. What is happening and what can you do?
Immature hepatic metabolic pathway (deficiency of UDP gluconuronate transferase) combined with a breakdown of fetal hemoglobin= build up of bilirubin. You can use photoTx (changes confirmation of Bilirubin to make it soluble)
What is Crigler Najjar Syndrome and how is it treated? Type I vs II
Type I complete absence of UDP glucuronyl transferase. -Causes Severe Hyperbilirubinemia that causes encephalopathy called Kernicturus **Tx liver transplant and blood transfusions Type II deficiency in UDP glucouronyl transferase **benign
what is Gilbert Syndrome?
Reduced activity of UDP GT 25%. Serum bilirubin is less than 6 mg/dL but may increase with fasting, stress or ETOH consumption.
(Correlation box) Sulfa drugs
--Sulfa drugs disrupt DNA replication in bateria as competitive inhibitor of the bacterial enzyme that incorporates p-aminobenzoic acid into folate
-won't affect human cells because we have to incorporate folate into our diet and don't make it ourselves
(correlation box) Methotrexate
- targets dihydrofolate reductase that converts dietary folate to the biologically active tetrahydrofolate in the liver
-disrupts DNA replication in cancer cells by inhibiting purine nucleotide synthesis
Specific Roles of nucleosides and nucleotides
ATP and GTP for energy (cosubstrates of reactions) Cofactors - CoA, FAD, FMN, UDP-Glc, NADPH, NADH Stabilization, regulatory elements - cAMP and cGMP Vitamins - B12
Oxidation levels of purines
Guanine, hypoxanthine=1 oxygen
xanthine= 2 oxygen
uric acid=3 oxygen, with limited aqueous solubility. Plays role in gout.
-SCID: arms of B and T cells are crippled. "Bubble boys"= need complete protection from environment.
-ADA: leads to high levels of ADENOSINE, which is converted to dATP, inhibits ribonucleotide reductase and formation of other dNDPs. DNA synthesis impaired. Immunocompromised.
(correlation box) gout
-high levels of uric acid in blood - by overproduction or under-excretion -sodium urate in joints=painful -kidneys= kidney damage -avoid diet rich in purines -colchicine=decrease movement of granulocytes to affected areas -allopurinol=inhibits xanthine oxidase, increase levels of more soluble purines hypoxanthine and guanine
(correlation boxes) uric acid levels as a diagnostic marker for gout
-male normal: 4 to 8.6 mg/dL
-female normal: 3 to 5.9 mg/dL
- serum levels > 9 mg/dL increased risk of gout
why is glucose vitally important? What tissues in particular use glucose?
because it is the only molecule used by the BRAIN and RBC's. Skeletal muscle uses it primarily.
what are the various fasting serum glucose levels?
Hypo <60 Normal 60-100 Hyper >100
which GLUT transporters are specific for which cells and what are their regular affinity?
GLUT 1, 3 general and Km of 1 (high affinity) GLUT 2 Pancreas and Liver relatively low afinity GLUT 4 Muscle and Fat, has a moderate afinity to glucose however it is activated by Insulin.
-enzyme responsible for conversion of adenosine to inosine
-when deficient: SCID (bubble boys)
-when excessive: Hemolytic anemia. Destruction of adenosine depletes adenine nucleotide pools and triggers premature RBC destruction
What is DM and what are the type?
serum glucose 126> mg/dl Type I: beta cells attacked and destroyed (autoimmine) no insulin Type II: insulin resistance (GLUT 4 transporter).
what is the strict definition of diabetes?
lots of urine output.
Patient Joe has been complaining of frequent urination. upon testing his fasting glucose he has a level of 80 mg/dL. what is one possible etiology
deficiency of ADH aka diabetes insipidus.
-Catalyzes oxidation of hypoxanthine to xanthine, and xanthine to uric acid.
-target of Allopurinol- helps treat hyperuricemia
what are the caloric values of Fats CHO Proteins ETOH
why is it important for glucose to be phosphorelated immediately upon entering the cell?
once it is phosphorelated it has a negative charge and is unable to pass through the hydrophobic membrane.
A person comes into the ED with slurred speech and an unsteady gate. They have not eaten anything in several days. How is it possible that this person's energy supplies are not completely depleted and they are able to function?
Their energy supplies are depleted. They are using ETOH as a form of energy but are dangerously low in energy stores.
Pyrimidine Nucleotide Catabolism: Which pyrimidines are degraded to be ketogenic? Glucogenic?
Ketogenic: Cytosine, uracil
what types of Rxns are anabolic processes? catabolic processes? where do anabolic processes get their energy?
anabolic--endergonic catabolic--exergonic anabolic processes get their energy from catabolic processes
what's the role of glycolysis in our health and well being? endergonic/exergonic? anabolic/catabolic?
Production of ATP Provides intermediates in other biosynthetic pathways (proteins, cholesterol, cell organelles) catabolic exergonic
What is the role of gluconeogenesisin our health and well being? endergonic/exergonic? anabolic/catabolic?
removes lactate from out blood stream, converted to pyruvate and generates glucose. -replenishes glycogen stores -maintains adequate glucose levels Endergonic anabolic
what is the role of the pentose-6phosphate system to the well being? endergonic/exergonic? anabolic/catabolic?
-produces ribose 5 phosphate (ribose for DNA synthesis). -Reduces NADP to NADPH which is used in Fatty Acid Synthesis and Cholesterol Sythesis. catabolic exergonic oxidative to the "glucose molecule" but reductive to NADP
what is the role of glycogen to our health and well being? What is special about the liver's ability to break down glycogen?
Keeps us from becoming hyperglycemic after meals or hypoglycemic between meals.
***has Glucose 6 phosphatase to remove the phosphate group and release it into the blood stream*** not many cells have this enzyme
what is the key molecule that connects all glucose pathways?
Glucose 6 phosphate
what can pyruvate be generated from?
what can Acetyl CoA be used for?
Production of cholesterol, ketone bodies and Fatty Acids.
De Novo Synthesis of Purine nucleotides
Glycine, Aspartate, and Glutamine involved
Assembled on ribose-5-phosphate scaffold from pentose phosphate pathway
Know that folic acid system associated with DNA synthesis
expensive: 4 ATP to generate IMP
what produces ATP faster, Aerobic or Anaerobic Glycolysis?
how does the RBC generate it's energy?
Through anaerobic glycolysis becuase there are no mitochondria.
-inhibits thymidylate synthase in syn of pyrimidines
-chemotheraputic agent; can't make DNA without thymine/derivatives
what pathway converts lactate to glucose? is there a net production of glucose? what about production of glucose from alanine
gluconeogenesis. No net production for lactate-->glucose Slight net production for alanine-->glucose
what is the net production of ATP from glucose both in aerobic conditions and anaerobic conditions?
aerobic 32 ATP anaerobic 2 ATP
-defect in (APRT) adenine phosphoribosyl-transferase in purine nucleotide salvage pathway
-deficiency in enzyme
-Adenine build up
-Due to deficiency, de novo synthesis of purines from more purines with PRPP
- Kidney stones
in a Fed States what happens to the insulin, glucagon and the various tissues
increased insulin decreased glucagon glycogenoesis in liver and skeletal muscle. triglycerides made in adipose and liver. Glucose taken up and utilized as fuel in other tissues (aerobically or anaerobically).
what does insulin do to glucagon and how does this effect someone who is a type one diabetic?
insulin blocks glucagon release. Type I patients do not have the beta cells-->no glucagon "blocking"-->glucagon working and enabling gluconeogenesis, and glycogen breakdown when it is not needed.
-defect in HGPRT enzyme in purine salvage pathway
-hyperuricemia and hyperuricosura (leading to gout) due to high circulating levels of hypoxanthine and guanine
-urate kidney stones
-feedback leading to more and more synthesis of purines than is needed
-in pyrimidine nucleotide salvage pathway
-Incorporates into rapidly dividing cells
-lacks 3'-hydroxyl group so it leads to the termination of DNA replication
-varicella, herpes zoster, genital herpes
Phase I of heme synthesis
-Succinyl CoA condenses with glycine to make ALA (aminolevulinic acid)
-ALA synthase: inhibited by heme and hemin, mRNA contains iron response element (not translated without iron present), vitamin B6 cofactor (deficiency causes anemia)
d-aminolevulinic acid dehydratase
condenses 2 aminolevulinic acids together -> porphobilinogen
(phase 2 of heme syn)
-enzyme in phase 2 of heme syn
-4 porphobilinogen⇒ hydroxymethylbilane (linear)
-3rd phase of heme syn
-adds Fe2+ to protoporphyrin IX to make heme
-disorders of heme synthesis
-acute hepatic porphyrias- neuro symptoms
-erythropoietic porphyrias- primary manifestations in skin w/ photosensitivity
Acute intermittent porphyria
-defective enzyme: porphobilinogen (PBG) deaminase (in liver)
-excessive production of ALA and PBG
-abd pain and neuro dysfunction
-defect in protoporphyrinogen IX oxidase
-photosensitivity and neurologic symptoms, devo delay in children
-defective enzyme: ferrochelatase
-photosensitive w/ skin lesions
-may have gallstones and mild liver dysfunction
-heme oxygenase removes bridge between pyrrole rings
- CO2 released
-Fe released as ferric (oxidized; Fe3+)
-GREEN biliVERDin synthesized
-induced by heme, metal ions, phenylhydrazine
Reductions of Biliverdin
-biliverdin reduced to bilirubin (red/orange) by biliverdin reductase
-Bilirubin transported to liver via serum albumin (unconjugated bilirubin is insoluble)
-Bilirubin conjugated with glucuronic acid in liver (soluble) by bilirubin-UDP glucuronosyl transferase (UDP-GT)
-conj bilirubin released as bile⇒small intestine⇒colorless urobilinogen
-some urobilinogen reabsorbed and transported to kidney; oxidized to urobilin (yellow pigment in urine)
-rest of urobilinogen⇒large intestine. Metabolized to stercobilin (brown in feces)
what hormones are released in the fasting state and what effect does that have on the body?
Glucagon released. Gluconeogenesis from protein breakdown in muscles and glycerol is converted to glucose. Fatty acids are oxidized. Alpha keto acids are a form of energy in the liver
what is the liver's preferred fuel?
Alpha keto acids and fatty acids
what is the enzyme that converts glucose to glucose 6 phosphate? regular cells and liver
hexokinase glucokinase in liver
what are the two phases of the pentose phosphate pathway?
I: creation of NADPH, and Ribose sugars II: nonoxidative reactions which can be made into ATP or send intermediates to gluconeogenic pathways.
what does red blood cell glucose 6 phosphate dehydrogenase deficiency cause?
If there is a deficiency of G6PD then there is no way for the Pentose Phosphate Pathway to work leaving a low level of NADPH and no way to reduce glutathione which is crucial to maintain the health of the RBC membrane. Triggered in the presence of an infection that is oxidative in nature
what is the problem with a deficiency in glucose 6 phosphatase or glucose 6 phosphate transport?
causes severe hypoglycemia because there is nothing to let the glucose out of the liver. Lactic Acidosis, which effects other tissues.
what energy stores does resting skeletal muscle use active skeletal muscle use
resting-lipids active skeletal-glucose.
how does the phosphorylation of glycogen synthase and glycogen phosphorylation.
phosphorilation of glycogen synthase inhibits glycogen synthesis. phosphorylation of Glycogen phosphorylase activates it promoates glycogen degregation
Where is each of these AA's made from:
Gly, Ala, Asp, Glu, His
Gly - 3-phosphoglycerate to Serine
Ala - Pyruvate
Asp - Oxaloacetate
Glu - AKG
Generally, how are amino acids synthesized?
Using transaminases to transfer and amine group onto a keto acid (derivates of G6P).
What about His, Serine family, and glutamate family?
His - from ribose 5-P from PPP
Ser - directly from 3-P-G
Glu - AKG + amine from Gln = Glu
Where are argenine and tyrosine from?
Arg - from urea cycle
Tyr - converted from Phe (essential)
Which AA's are strictly ketogenic? Pneumonic? What do they form? What do they make from there?
Leu and Lys
"Leucy Lykes fatty foods"
Ketone bodies, FA's, isoprenoids
Which AA's are both ketogenic and glucogenic?
Ile, Trp, Phe, Tyr, Thr
"PITTT collects all"
What do strictly glucogenic AA's form? Precursors for what?