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391 Cards in this Set

  • Front
  • Back
How are dietary proteins broken down?
What aa residue of Ub does Ub attach on?
K48
What does E1 do?
adenylates Ub
What does E2 do?
carries Ub
What does E3 do?
transfers Ub from E2 to target protein
Velcade (bortezomib)
proteasome inhibitor for myeloma and lymphoma
What is the first step in amino acid degradation?
transamination
transamination
What is the second step in amino acid degradation?
oxidative deamination
oxidative deamination
What are AST and ALT used for?
aspartate aminotransferase and alanine aminotransferase
used for heart attack diagnosis
What coenzyme do aminotransferases use?
pyridoxal phosphate
What coenzyme does H decarboxylase use?
pyridoxal phosphate
What coenzyme does glycogen phosphorylase use?
pyridoxal phosphate
What is frequently produced in transamination reactions?
E from alpha-ketoglutarate
What determines if an amino acid is non-essential?
If the alpha keto acid derivative can be synthesized
What happens to the N transferred to the alpha ketoglutarate?
glutamate dehydrogenase uses NADPH to release ammonium
What regulates glutamate dehydrogenase?
GTP inhibits formation of TCA intermediates
ADP activates
Where does the glutamate dehydrogenase reaction work?
liver
What does the alanine cycle do?
Carries nitrogen from extrahepatic E to the liver where it is deaminated by alpha ketoglutarate to allow urea synthesis
What does glutamine synthase do?
adds ammonium to E using ATP so N can be carried through the blood
What is a major source of ammonia?
AMP -> IMP using adenylate deaminase
What is the most common cause of metabolic myopathy?
adenylate deaminase deficiency
What does adenosine deaminase deficiency cause?
severe combined immunodeficiency
What 3 amino acids are important to ammonia conversion?
A, E, Q
What happens to A as it arrives to the liver?
deaminated by A aminotransferase and the resulting glutamate is deaminated to produce ammonium
What happens to Q as it arrives to the liver?
deaminated by glutaminase to produce E which is deaminated to produce more ammonium
Where does the urea cycle occur?
liver
What is the first step in the urea cycle?
in mitochondria
uses 2 ATP
in mitochondria
uses 2 ATP
How does carbamoyl phosphate exit the mitochondria?
combines with an ornithine via ornithine transcarbamoylase that enters the mt to form citrulline, which exits the mt
What do citrulline and D form?
argininosuccinate via argininosuccinate synthase
uses ATP
What does argininosuccinase do?
cleaves fumarate from argininosuccinate to produce R
What does arginase do?
Cleaves urea from R to produce ornithine
What enters the urea cycle?
ammonia and aspartate
What exits the urea cycle?
fumarate and urea
How are the urea and TCA cycles linked?
argininosuccinase produces fumarate
What does glutamate produce in the brain?
decarboxylated to GABA
How does hyperammonemia affect glutamine?
increase
How does high ammonia affect pyrimidine levels?
increase
What is the most common urea cycle deficiency?
ornithine transcarbamoylase
x-linked
What happens with argininosuccinate synthetase deficiency?
causes citrulline buildup, need R supplementation
What happens in argininosuccinase deficiency?
argininosuccinate buildup, need R supplementation
What happens in arginase deficiency?
CNS disorder
R exclusion diet
Which 2 amino acids are solely ketogenic?
L K
Which 4 amino acids are keto and glucogenic?
FYIW
Which amino acids are essential?
MLK HIV WTF
What is the recommended daily allowance of protein?
50 g
What causes positive nitrogen balance?
growth, pregnancy
How is S synthesized?
3-PG (glycolytic intermediate) is oxidized by NAD+, aminated by glutamate, then dephosphorylated
How is G synthesized?
S -> G by serine hydroxymethyltransferase
produces 5-10-methylene-THF
What cofactor does serine hydroxymethyltransferase use?
THF
What disorders is folate deficiency associated with?
megaloblastic and pernicious anemia, neural tube defects, heart disease, cancer
How much folate do you need per day?
400 micrograms
What is the main biochemical function of folate?
one C transfer
What processes is folate necessary for?
nucleotide biosynthesis
S, G, H biosynthesis
methionine regeneration
Which atoms of THF are reactive?
N5 and N10
What 5 one C units are transferred by THF?
methyl, methylene, formyl, formimino, methenyl
sulfanilamide
antibiotic against folic acid synthesis enzyme
antimetabolite of PABA
What is the role of polyglutamylation of folate?
folate polyglutamates are retained in the cell
What is the active form of folate?
THF
What are the 3 major single C donors to folate?
G, S, H
What is the main route of G metabolism?
THF -> 5,10-methylene-THF
How many molecules of 5,10-methylene-THF are formed from serine?
2
What is methyl-THF used for?
methylate homocysteine to methionine
uses B12
Why is methionine regeneration necessary?
for SAM production, which is involved in methylation
Rank the contribution of amino acids into the folate pool
S > G >> H
What does DHFR do?
NADPH-mediated reduction of folate to THF
catalyzes twice
aminopterin and amethopterin
methotrexate
inhibit DHFR
raltitrexed
inhibitor of thimidylate synthase
pemetrexed
inhibits thimidylate synthase, DHFR, GARFT (de novo purine biosynthesis)
What does thimidylate synthase do?
methylates dUMP to dTMP
name these:
name these:
uracil thymine
5-FU
suicide inhibitor of thymidylate synthase
How is SAM synthesized?
ATP is hydrolyzed to bind methionine + adenosine
What does DNA methylation do?
Protects it from restriction enzymes and silences gene tx
What catalyzes methionine regeneration?
methionine synthase
How is cysteine produced?
homocysteine + serine by cystathionine beta-synthase
What cofactor does cystathionine beta-synthase use?
PLP
What 3 enzyme deficiencies cause homocystinuria?
cystathionine synthase, methionine synthase, methylene-THF reductase
How does folate deficiency cause ds DNA breaks?
uridylate is misincorporated into DNA instead of thymidylate
uracil is excised out
if two are excised close too each other
What intermediate is formed when H donates a C to THF?
forminino-THF
formaldehyde + THF
methylene-THF
What does homocystinuria cause?
mental retardation
Hyperhomocysteinemia causes what disease?
vascular
Folate trap
When cobalamine is deficient, methionine synthase cannot use methyl-THF so all the folate funnels to it.
What 2 symptoms make up pernicious anemia?
CNS defecit
megaloblastic anemia
What causes pernicious anemia?
cobalamine deficiency
Which symptoms of cobalamine deficiency can be fixed with folate supplementation?
megaloblastic anemia
How is histamine formed?
H reacted with H decarboxylase
What cofactor does H decarboxylase use?
pyridoxal phosphate
What do histamines do in the stomach?
secrete stomach acid
cimetidine
histamine receptor antagonist
PKU
phenylalanine hydroxylase deficiency
What is the coreductant for F oxidation to Y?
tetrahydrobiopterin
Albinism
Lacking melanin pigments, synthesized from Y
How is NO produced?
R -> citrulline using NO synthase, O2 and NADPH
Maple syrup urine disease
oxidative decarbox of alpha-ketoacids from V, I, and L are blocked
Salvage pathway for nucleotides
base attached to activated ribose (PRPP)
PRPP synthetase
catalyzes ribose 5 P activation using a pyrophosphate from ATP
What is the committed step in de nove purine biosynthesis?
PRPP amination to 5-phosphoribosylamine by Q phosphoribosyl amidotransferase
What molecules are used in de novo purine biosynthesis?
D, CO2, G, 2x Q, ribose-P, 10-formyl-THF
What is the initial product of de novo purine biosynthesis?
IMP
What inhibits the first reaction of de novo purine biosynthesis?
pemetrexed
What high energy substrate is used to catalyze IMP -> AMP?
GTP
How many enzymes in IMP synthesis have folate derivatives?
2 (10-formyl-THF)
What 2 precursors contribute C atoms to pyrimidine biosynthesis?
carbamoyl phosphate, aspartate
What enzyme catalyzes the first step in de novo pyrimidine biosynthesis?
carbamoyl phosphate synthetase II
What are the main subunits of cabamoyl phosphate synthetase?
glutamine hydrolysis to produce ammonia
bicarbonate phosphorylation to produce caboxyphosphate
carbamic acid phosphorylation to product carbamoyl phosphate
What make up CAD?
CPSII, aspartate transcarbamoylase, dihydroorotase
Know generally the steps from carbamoyl phosphate to orotate
leflunomide
inhibits de novo synthesis of pyrimidine nucleotides at dihydroorotate dehydrogenase
What is PRPP?
activated ribose that can accept nucleotide bases
orotate + PRPP =
orotidylate
What makes up UMP synthase?
orotate phophoribosyltransferase and orotidylate decarboxylase
hereditary orotic aciduria
anemia, growth retardation
deficient UMP synthase
treat with exogenous uridine
What inhibits CPSII?
UTP
What converts nucleoside monophosphates to diphosphates?
specific nucleoside monophosphate kinases
How to get CTP from UTP?
amination using Q and ATP
thymidylate synthase
one C transfer from 5,10-methylenetetrahydrofolate to dUMP, results in DHF, NADPH mediated
How to go from UMP to dUMP?
ribonucleotide reductase
What inhibits thymidylate synthase?
5 fluorouracil via suicide inhibition
What is the in vivo version of fuorouracil?
fluorodeoxyuridylate
What enzyme is important in salvage pathway of nucleotide biosynthesis?
phosphoribosyltransferase
dihydroorotate dehydrogenase
dihydroorotate to orotate
hypoxanthine-guanine phosphoribosyltransferase
HGPRTase can act on guanine or hypoxanthine to form GMP/IMP
What do salvage reactions do?
Form nucleotides from free bases
Erythrocytes salvage which pyrimidines?
orotate, uracil, thymine but not cytosine
HGPRT deficiency
Lesch-Nyhan syndrome
compulsive self injury, mental deficiency
hyperuricemia and high PRPP
What are NAD+, FAD derivatives of?
ATP
pellagra
low nicotinate and W
dermatitis, dementia, diarrhea
What is the common feature of NAD, FAD, CoA biosynthesis?
AMP transfer
What is the substrate for ribonucleotide reductase?
What catalyzes the committed step in purine nucleotide biosynthesis?
glutamine phosphoribosyl amidotransferase catalyzes conversion of PRPP into phosphoribosylamine
What inhibits glutamine phosphoribosyl amidotransferase?
AMP, GMP, IMP
Where does AMP/GMP inhibit the de novo pathway?
PRPP amidotransferase
Describe regulation after inosinate production?
Inosinate can become either AMP or GMP, both of which are feedback inhibited
What inhibits ribonucleotide reductase?
dATP by allostery, ATP reverses the inhibition
What are the regulatory steps in pyrimidine synthesis?
nuclease
nucleic acid to nucleotide
How is AMP degaded?
AMP -> adenosine deaminated by adenosine deaminase to inosine -> lose ribose to hypoxanthine -> oxidized by xanthine oxidase to xanthine -> oxidized again to uric acid/urate
What is the benefit of having high urate?
ROS scavenging
What does adenosine deaminase deficiency cause?
severe combined immunodeficiency
gout
urate deposition disease
sodium urate crystals form in joints and cause arthritis
allopurinol
inhibits xanthine oxidase to decrease urate
How to differentiate between hyperuricemia from overproduction of purines or excessive cell death/kidney disease?
by radiolabeling protein synthesis and seeing if new urate has the radiolabel
What is a positive effector for glutamine-PRPP amidotransferase?
PRPP
What biochemical effect does decreased HGPRTase have?
increased intracellular PRPP, decreased IMP/GMP, allows hypoxanthine/xanthine to be scavenged to IMP/XMP
What are pyrimidines broken down to?
beta amino acids, ammonium
What process produces beta-aminoisobutyrate?
thymine degradation
What patients have high beta-aminoisobutyrate?
cancer patients undergoing chemotherapy
What are the two alcohol metabolizing systems?
liver alcohol dehydrogenase
liver microsomal ethanol oxidizing systems
What are some acute effects of alcohol?
hypoglycemia
ketoacidosis
lacticacidosis
What are some long term effects of alcohol?
liver disease
acetaldehyde adducts
free radical damage
What other alcohols are metabolized?
methanol
ethylene glycol
What is ethylene glycol in?
antifreeze
brake fluid
What happens when you ingest ethylene glycol?
acidosis
kidney damage
Where is ethanol metabolized?
<5% in upper GI
90% liver
up to 10% excreted by lungs/kidney
What is the toxic intermediate of ethanol metabolism?
acetaldehyde
Draw ethanol metabolism from ethanol to CO2:
What coenzyme is used by alcohol dehydrogenase?
NAD+
How is acetaldehyde metabolized?
acetaldehyde dehydrogenase takes it to acetic acid
How do the two ALDH isoforms differ?
ALDH2 is mitochondrial and catalyzes 80% of acetaldehyde oxidation
ALDH1 is cytosolic and oxidizes multiple aldehydes
What is significant about the ADH2*2 allele?
ADH catalyzes ethanol too quickly to acetaldehyde that ALDH cannot keep up and acetaldehyde build up.
Where are Class I ADH expressed?
liver
Where are Class IV ADH expressed?
upper GI tract
What happens with excess acetaldehyde?
nausea and vomiting
What is significant about ALDH2*2?
ALDH has little activity
acetaldehyde accumulates
Disulfiram
ALDH inhibitor
What happens to the acetate that is produced from ALDH?
Where is MEOS found?
microsomal ethanol oxidation system
liver
What is the main enzymes in MEOS?
CYP450 enzyme CYP2E1
When is MEOS used?
at high alcohol concentration
What is the metabolic flaw of MEOS?
produces acetaldehyde too fast
byproduct of free radicals
uses up NADPH which is needed to regenerate reduced glutathione
Why is taking acetaminophen dangerous for alcoholics?
CYP2E1 converts acetaminophen to NAPQI an unstable oxidant
Why is taking phenobarbital and ethanol dangerous?
Phenobarbitals induce CYP2B1/2, which metabolize phenobarbital, but ethanol inhibits these enzymes and phenobarbital can accumulate to toxic levels.
What is the energy yield for ethanol using ADH?
+5 from 2x NADH produced in etOH -> acetate
-2 from acetate -> acetyl CoA
+10 from acetyl CoA
net +13
What is the energy yield of etOH using MEOS?
-2.5 from NADPH use of CYP2E1
+2.5 from acetaldehyde -> acetate
-2 from acetate -> acetyl CoA
+10 from acetyl CoA
net +8
empty calories
metabolic energy with few nutrients
like liquor, processed foods
How does alcoholism cause vitamin deficiency?
alcohol damages cells lining GI system
damages liver and its ability to store nutrients
especially thiamine (B1), riboflavin (B2), pyidoxine (B6), ascorbic acid, folic acid
What does alcohol-related thiamine deficiency cause?
Wernicke-Korsakoff syndrome
encephalopathy
psychosis
What does thamine do?
vit B1 -> TPP
cofactorfor: PDH, alpha KG DH, branched chain alpha-ketoacid DH, transketolase
List 6 reversible metabolic effects of etOH:
inhibition of FA oxidation
activation of TAG synthesis
fatty liver
ketoacidosis
lactic acidosis
hypoglycemia
List 7 irreversible effects of etOH:
acetaldehyde adducts
free radicals
inflamed liver with cell death
disrupted blood flow
cirrhosis
loss of liver function
hepatic failure
What %age of autopsies have alcohol-induced cirrhosis?
10%
What is the peak incidence age of etOH toxicity?
40-55
What 3 forms of liver disease occur from alcohol?
fatty liver
hepatitis
cirrhosis
What is the main metabolic side effect of etOH metabolism?
increased NADH/NAD+ ratio
What consequences does high NADH/NAD+ have?
inhibits FA oxidation
inhibits TCA cycle
FA synthesis
ketoacidosis
lactic acidosis
low GNG due to blocking pyruvate formation from alanine, lactate
What does acetaldehyde do in the liver?
- prevents protein secretion from by forming adducts with proteins and microtubules
- binds reduced glutathione
- lipid peroxidation
How does ROS affect acetaldehyde?
ROS inhibits eTC and limits NAD+ formation, to increase acetaldehyde
What hepatic enz are measured in the serum to detect hepatocyte damage?
A aminotransferase ALT
D aminotransfer AST
What is the main problem following liver acetaldehyde adduct formation?
The products are denatured and cannot be secreted, causing osmotic imbalance and subsequent swelling of the liver, causing portal hypertension and esophageal verices.
What is the main source of free radicals in etOH metabolism?
CYP2E1
Why is CYP2E1 a good source for free radicals?
leakage from FMN and heme
What free radicals does CYP2E1 produce?
hydoxyethyl radical, superoxide
What is the main target of free radicals?
membrane lipids, especially on the inner mitochondrial membrane
cardiomyopathy from alcohol
acetaldehyde and malondialdehyde adducts target heart proteins and weaken it, highly dependent on energy production
What are the products of meOH metabolism?
What are the products of ethylene glycol metabolism?
Why is ethylene glycol metabolism so toxic?
It produces intermediates with 2 hydroxyls
acidemia
oxalate crystals -> kidney damage
4-MP
fomepizole, antizol
inhibitor of ADH
Why is oxalic acid dangerous?
Calcium oxlate can precipitate in kidneys and cause kidney stones
Oxalate chelates calcium
Why is it important to screen kidney stones for calcium oxalate?
some people need to avoid oxalate foods because of its kidney stone forming tendencies
Why doesn't muscle glycogen buffer blood glc?
muscles lack glc 6 phosphatase
When is glycogen especially important to cardiac muscle?
myocardial infarction
What organ has the highest concentration of glycogen?
liver
What tissue has the highest mass of glycogen?
skeletal muscle
How are glc molecues attached in glycogen?
alpha 1,4 in straight chain
alpha 1,6 in branch
Where does glycogen breakdown or synthesis begin?
non-reducing end
What is the purpose of glycogen branching?
Increase solubility, allow for multiple glycogen breakdown sites
How many glc residues b/w branches?
10
What is the advantage to high MW glycogen?
Doesn't contribute to osmtoic pressure
What enzyme catalyzes glycogen breakdown?
glycogen phosphorylase
What enzyme catalyzes glycogen synthesis?
glycogen synthase
Draw glycogenesis:
What transports glc into liver? muscle?
liver - GLUT2
muscle - GLUT4
What enzyme interconverts glc 1 P and glc 6 P?
phosphoglucomutase
What is the predominant product of glc6P in muscle?
lactate
gluco/hexokinase?
Glucokinase is found in the liver and beta cells and has a lower affinity for glc than hexokinase. Glc6P inhibits hexokinase.
MODY
maturity onset diabetes in the young
glucokinase disorder
inadequate insulin secretion upon glc stimulation
What is the first step in glycogenesis?
glc must be activated as UDP glc
glc must be activated as UDP glc
What enzyme catalyzes the elongation of glycogen chains?
Where is ATP used in glycogen synthesis?
Converting UDP -> UTP to produce UDP-glc
glycogenin
primer for glycogen synthesis
once enough glc's are added, it becomes cleaved off to start anew
What is the minimum glc residues inb/w branches?
4
What is the mechanism of glycogen branching?
Once a 7 glc residue is free, a branching enzyme moves it to an alpha 1,6 spot
Once a 7 glc residue is free, a branching enzyme moves it to an alpha 1,6 spot
What effect does insulin have on glycogenesis?
increase
What effect do glucocorticoids have on glycogenesis?
decrease
lysosomal alpha 1,4-glucosidase
small quantity of glycogen is broken down by lysosomes
How does glycogen debranching work?
phosphorylase cleaves glc no closer than 4 glc from a branch
debranching enzyme (alpha 1,6 glucosidase) moves 3 glc units and hydrolyzes 1 glc
What is the normal glc1P:glc ratio?
10:1 because there are usually 10 glc b/w branches and nonP glc is produced from branch points
How to go from glc1P to glc?
What effect do glucagon and epinephrine have on glycogen metabolism?
GPCR/cAMP/PKA in liver to activate glycogenolysis by phosphorylase a and inhibiting glycogen synthase b. It also inhibits protein phosphatase 1 which reveres PKA.
What activates protein phosphatase 1?
Insulin
Is dephosphorylated glycogen synthase b active or inactive?
inactive
How does activated protein phosphatase 1 affect glycogen synthase b and phosphorylase b?
dephosphorylate both of them to activate GS and deactivate phosphorylase
How do glucocorticoids affect glycogen metabolism?
induce glycogen breakdown
What are downstream effects of glucocorticoids?
induced: GNG, glycogen synthase, proteolysis by Ub
repressed: glycolysis, glucokinase, glycogen phosphorylase
How is phosphorylase kinase activated?
hormones/PKA or Ca activate glycogenolysis
hormones/PKA or Ca activate glycogenolysis
How does glc affect phosphorylase in hepatocytes?
allosteric inhibition
phosphorylase a/b, which is active?
a
von Gierke disease, type I
glc-6-phosphatase deficiency
liver is overloaded with glycogen
hyperlipidemia, lactic acidosis
Pompe disease, type II
lysosomal alpha 1,4-glucosidase deficiency
glycogen accumulation in lysosomes
Cori disease, type III
debranching enzyme deficiency
hypoglycemia due to inefficient glycogen usage
affects muscle, liver
Andersen disease, type IV
branching enzyme deficiency
affects liver
long glycogen branches cause inefficient storage and usage of glycogen
What are the basic functions of the pentose phosphate pathway?
glc oxidation to produce NADPH
produce ribose 5 P
interconvert pentose sugars
What is NADPH used for?
Reductive biosynthesis of FA, nt's, NTS, cholesterol
Detox - regenerating glutathione and CPY450
What does ribose 5 P produce?
nucleic acids, ATP, NADH, FAD, CoA
What do the two phases of the pentose phosphate pathway do?
oxidative starts with glc6P to produce NADPH
the nonoxidative phase interconverts different sugars
How many NADPH per glc 6 P?
2
What is the first rxn in the pentose phosphate pathway?
NADPH producing
NADPH producing
Does glc 6 P dehydrogenase ever reduce NAD+?
no
What happens to 6-P glucono-delta-lactone?
hydrolyzed by lactonase
hydrolyzed by lactonase
What happens to 6 P gluconate?
oxidative decarboxylation to produce more NADPH
oxidative decarboxylation to produce more NADPH
What is the key intermediate in the pentose phosphate pathway?
ribulose 5 P
In order to produce nucleotides, what intermediate does ribulose 5 P convert to?
ribose 5 P
ribose 5 P
What is ribulose 5 P epimerized to?
xylulose 5 P
Fundamentally, what does transketolase do?
transfers 2C glycoaldehyde from a ketose to an aldose
transfers 2C glycoaldehyde from a ketose to an aldose
What coenzyme does transketolase use?
TPP
What intermediates do xylulose 5 P and ribose 5 P produce?
glyceraldehyde 3 P and sedoheptulose 7 P
What enzymes use TPP?
transketolase
PDH
alpha KG DH
Fundamentally, what does transaldolase do?
transfers 3C unit from ketose to aldose
transfers 3C unit from ketose to aldose
What amino acid residue is involved in the transaldolase mechanism?
K
What two intermediates can ribulose 5 P go to?
ribose 5 P or xylulose 5 P
What do erythrose 4 P and xylulose 5 P produce?
fructose 6 P and glyceraldehyde 3 P
fructose 6 P and glyceraldehyde 3 P
What is the net product of the nonoxidative phase?
in: ribose 5 P, 2x xylulose 5 P
out: 2x fructose 6 P, glyceraldehyde 3 P
How to diagnose thiamine deficiency?
Measure RBC transketolase activity +/- thiamine, should be no change if the diet is adequate in thiamine
What disease does thiamine deficiency cause?
beri-beri
What step of the pentose phosphate pathway is controlled? What controls it?
glc 6 p dehydrogenase
NADP+ availability, NADPH can outcompete it
What forms of glc 6 p dehydrogenase are active?
dimer and tetramer
monomer is inactive
What does NADP+ binding to glc 6 p dehydrogenase do?
dimer and tetramer formation
What are the four pathways glc 6 p can go in?
glycolysis
pentose phosphate pathway
glycogenesis
blood glc (liver)
When is ribose 5 p needed more than NADPH?
during DNA replication (G1 phase)
What happens to glc 6 p during G1?
glycolysis because DNA replication demands more ribose 5 p
When are both ribose 5 p and NADPH needed?
Concurrent nt and FA synthesis in mitotic cells
What is the fate of glc 6 p during nt and FA synthesis demand?
Just the oxidative phase produces 2x NADPH and ribose 5 P
When do you require NADPH but not ribose 5 p?
detox, free radical crisis
What happens to glc 6 p during free radical crisis?
Both the oxidative and nonoxidative pathways are on so NADPH can keep being reproduced alongside glycolysis and GNG
When is NADPH and ATP required?
cholesterol or FA synthesis
What is the fate of glc 6 p during cholesterol synthesis?
oxidative and nonoxidative ppp, along with glycolysis to produce pyruvate/ATP
What is reduced glutathione used for?
defense against oxidative stress
electron donor
maintains reducing conditions in rbc
How much reduced glutathione exists in animal cells?
5 mM
What is the ratio of reduced:oxidized glutathione?
500:1
What is the reactive part of glutathione?
sulphydryl group
What is oxidized glutathione?
2 glutathione molecules that are connected via disulfide bond
What is the molecular mechanism of glutathione reduction by glutathione reductase?
NADPH electrons are transfered to FAD+ to cysteines to glutathione
NADPH electrons are transfered to FAD+ to cysteines to glutathione
What cells really need reduced glutathione?
RBC
maintain reduced Hb and ferrous Fe
What does defective pentose phosphate pathway cause in rbc's?
denatured Hb in rbc (Heinz bodies)
What do glutathione peroxidases do?
reduces lipid hydroperoxides to alcohols
reduces hydrogen peroxide to water
reduces lipid hydroperoxides to alcohols
reduces hydrogen peroxide to water
What is the active residue in glutathione peroxidase?
selenocysteine
What does misfolding cause glutathione peroxidases to do?
aggregate via disulfide bond formation
How do Heinz bodies affect rbc's?
Increase likelihood of lysis
list 4 causes of haemolytic anemia
rbc membrane defects (hereditary spherocytosis)
abnormal Hb (thalassemia)
abnormal glycolytic enzymes including glc 6 p DH (non-spherocytic hemolytic anemia)
oxidative stress
How common is glc 6 p DH mutation?
7%, commonly in Africa, South Asia, and Mediterranean
Why is glc 6 p DH good?
protects against malaria by Plasmodium falciparum
What does glc 6 p DH cause?
hemolytic anemia
What induces hemolytic anemia in glc 6 p DH mutant patients?
antimalarial drugs, sulfa drugs, fava beans, infections
What does a Beutler fluorescent test measure?
Detects deficiency in glc 6 p DH via rbc NADPH production by UV (365 nm)
What patients produce a false positive Beutler fluorescent test?
Actively hemolytic patients produce high fluorescence even though they are deficient
What causes MetHb?
antimalarial drugs - pamaquine, primaquine
antibiotics - trimethoprim, sulphonamides, dapsone
What is MetHb?
Fe 3+ oxidized Hb
How do fava beans cause hemolytic anemia?
Produces vicine which damages rbc membranes and produces peroxide
What treatments are used for glc 6 p DH deficiency?
vaccination to reduce infections
self limiting
avoiding certain drugs
blood transfusions
splenectomy/bone marrow transplant for extreme cases
Why does glc 6 p DH cause hemolytic anemia?
less NADPH to regenerate reduced glutathione
Heinz bodies form on rbc membranes
continued generation of superoxides and lipid peroxides
less NADPH to regenerate reduced glutathione
Heinz bodies form on rbc membranes
continued generation of superoxides and lipid peroxides
What is another name for tylenol/acetaminophen?
Paracetamol
What is the most common cause of acute liver toxicity?
tylenol overdose
What is produced in excess during tylenol overdose?
NABQI -> free radical damage to liver
How to treat acetaminophen overdose?
N-acetylcysteine to restore reduced glutathione
How is acetaminophen metabolized?
glucuronidation and sulfation produce excretable products
CYP-mediated hydroxylation produces toxic NAPQI which conjugates with nucleic acids, proteins, and lipid membranes
What is the basic structure in porphyrins?
pyrrole
pyrrole
What is bilirubin broken down to?
urobilins in urine
stercobilin in feces
What is the major porphyrin in humans?
heme
What proteins use heme?
Mb, Hb, ER and mitochondrial cytochromes, catalase
What is a prosthetic group?
a tight-bound non-peptide component of proteins
What is the first tetrapyrrole ring that is formed in heme synthesis?
uroporphyrinogen III
What rxn is catalyzed by ALA synthase?
succinyl CoA and glycine decarboxylation to ALA
succinyl CoA and glycine decarboxylation to ALA
What coenzyme does ALA synthase need?
PLP
What is the rate-limiting step in porphyrin synthesis?
ALA synthase
What allosterically inhibits ALA synthase?
hemin and heme
What is hemin?
oxidized heme
oxidized heme
Can hemin carry oxygen?
no
What vitamin is PLP derved from?
B6 (pyridoxine)
What are the major anaplerotic molecules for the TCA cycle?
glc, alanine, lactate, citrate, branched amino acids
How many succinyl CoA's are req'd for one heme?
8
What rxn is catalyzed by ALA dehydrase?
2 ALA molcules to porphobilinogen containing a pyrrole ring
2 ALA molcules to porphobilinogen containing a pyrrole ring
What side chain is important for ALA dehydrase?
sulfhydryl
What metal is used by ALA dehydrase?
Zn
What inhibits ALA dehydrase?
Pb
How do ALA and porphobilinogen affect the brain?
neurotoxin
What rxn is catalyzed by porphobilinogen deaminase
linear tetrapyrrole formation from 4 porphobilinogens to methylbilane or polypyrryl methane
linear tetrapyrrole formation from 4 porphobilinogens to methylbilane or polypyrryl methane
How are the acetate and propionate side chains of porphobilinogen oriented?
symmetric
APAPAPAP
What rxn is catalyzed by uroporphyrinogen synthase?
uroporphyrinogen III tetrapyrrole ring formation
uroporphyrinogen III tetrapyrrole ring formation
What is the acetate and propionate orientation of uroporphyrinogen III?
asymmetry
APAPAPPA
What is uroporphyrinogen I?
symmetric uroporphyrinogen produced spontaneously with a genetic defect in uroporphyrinogen synthase
What rxn is catalyzed by uroporphyrinogen decarboxylase?
decarboxylation of sidechains of uroporphyrinogen III to coproporphyrinogen III (acetyl -> methyl)
How is protoporphyrin IX synthesized?
Coproporphyrinogen III is propionyl side chain-decarboxylated to vinyl and ring-oxidated
What catalyzes the last rxn in heme synthesis?
ferrochelatase
ferrochelatase
Ohter than heme, what is another metaloporphyrin?
cabalamin (B12)
What substitutions does active cobalamin have?
5'-deoxyadenosine or methyl
How is heme synthesis compartmentalized?
ALA leaves the mitochondria and coproporphyrinogen III enters back in
ALA leaves the mitochondria and coproporphyrinogen III enters back in
How do heme and hemin regulate heme synthesis?
ALA synthase precursos synthesis, transport into the mitochondria, and activity
What is one of the most difficult environmental problems to control?
lead poisoning
How does lead poisoning manifest itself in adults?
fatigue, abdominal pain, arthralgia
How does lead poisoning manifest itself in children?
encephalopathic crisis
What biochemical effects does lead poisoning have?
inhibits ALA dehydrase and ferrochelatase
forms zinc protoporphyrin
What do most porphyrias share?
photosensitivity
Which porphyrias do not induce photosensitivity?
ALA dehydrase and AIP
What symptoms come with porphyrias?
psychiatric problems and abdominal pain
What causes AIP?
Partial loss (50%) of porphobilinogen deaminase
What is the problem in AIP?
Accumulation of ALA and porphobilinogen
What symptoms are seen in AIP?
ab pain
seizures
agitation
mental disturbance
insomnia
constipation
tachycardia
high BP
parasthesia
dark red urine
What are porphyria patients often misdiagnosed with?
psychiatric disorder
How ti diagnose AIP?
elevated urine PBG and ALA
porphobilinogen deaminase in rbc's
no photosensitivity
porphyrins not elevated
How do some drugs worsen AIP?
CYP450 inducing drugs drain the heme supply and build up ALA and PBG
How to treat AIP?
withdraw CYP450 inducing drugs
administer hematin to inhibit ALA synthase (hemin)
carb rich diet inhibts ALA synthase
What causes congenital erythropoietic porphyria?
Mutated uroporphyrinogen synthase
What is bad about congenital erythropoietic porphyria?
methylbilane -> uroporphyrinogen I and its metabolites accumulate
What symptoms come with congenital erythropoietic porphyria?
skin blisters
ulcerating vesicles
scarring
hemolytic anemia
spleen enlargement
red urine
Where is heme catabolized?
spleen (70%)
liver
bone marrow
What is the first enzyme in heme catabolism?
heme oxygenase
heme oxygenase
What byproducts does heme oxygenase produce?
iron, carbon monoxide, NADP+
Why is CO toxic?
binds to Hb and complex IV of eTC
What is the function of bilirubin?
antioxidant
While bound to albumin in blood each molecule can destroy two hydroperoxy radicals
What is oxidized bilirubin?
biliverdin
How is biliverdin reduced back to bilirubin?
biliverdin reductase
biliverdin reductase
What free radical-related processes depend on NADPH?
glutathion reduction
heme oxygenase
biliverdin reductase
What are the different colors of bruises?
How is bilirubin made water soluble?
conjugation with 2x glucuronic acid on proprionate side chains to form bilirubin diglucuronide
conjugation with 2x glucuronic acid on proprionate side chains to form bilirubin diglucuronide
Where does bilirubin conjugation take place?
liver
What happens to bilirubin in case of liver damage?
water insoluble bilirubin accumulates in blood and fatty tissue like subcutaneous fat

jaundice
What are synonyms of soluble bilirubin?
bilirubin diglucuronide
conjugated bilirubin
direct bilirubin
What are synonyms of insoluble bilirubin?
bilirubin
unconjugated bilirubin
indirect bilirubin
How is bilirubin excreted?
UBG -> oxidized in blood -> urobilins
UBG -> oxidized in large intestine -> stercobilin
UBG -> oxidized in blood -> urobilins
UBG -> oxidized in large intestine -> stercobilin
What are possible causes of yellow skin in jaundice?
beta-carotene
lycopene
bilirubin
What causes prehepatic jaundice?
excessive hemolysis
What causes hepatic jaundice?
defective transport
lack of UDP-glucuronyltransferase
liver dysfunction
What causes posthepatic jaundice?
biliary obstruction
Lactate threshold
Point at which blood lactate accumulates above resting levels
OBLA
onset of blood lactate accumulation, point at which exercise intensity is such that lactate cannot be cleared at the rate it is produced
What are mean energy req's?
40 kcal/kg body
What are the recommend macronutrient guidelines?
60% carb
15% protein
25% fat
What is the max amount of protein that should be consumed?
No more than 1 g per lb body weight
How much Ca per day?
1200 - 1500 mg
How high can sweat rates be?
2 L / hr
What are the benefits to sodium for athletes?
maintains plasma osmolarity
reduces urine output
induces thirst
What is classic carb loading?
2 exhaustive sessions to blank glycogen
fat/protein diet for 3 d while training
high carb diet for 3 d with rest
What is modern carb loading?
regular diet with 75% VO2 max/90'
high carb diet with light exercise 2d
high carb diet with 1d rest
When does plasma caffeine peak?
40 - 60'
What is caffeine's half-life?
3 - 5 hr
What metabolizes caffeine?
liver
How quickly is caffeine absorbed?
90% within 20'
What effects does caffeine have?
mobilize intracellular Ca
augment catecholamine
spare adenosine by blocking adenosine receptors
enhance lipolysis
stimulate contractility
What adverse effects does caffeine cause?
restless
nervous
insomnia
tremors
hyperesthesia
diuresis
anorexia