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Biochem
subject review, based on kaplan lecture notes
99
Medical
Graduate
04/21/2010

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Term
glucose transporters on most tissues, basal glucose uptake
Definition
GLUT 1 and GLUT 3
Term
glucose transporters on liver, pancreatic B cells
Definition
GLUT 2
Term
glucose transporters on skeletal muscle and adipose tissue, insulin-dependent
Definition
GLUT 4
Term
RDS glycolysis
Definition
PFK-1
Term
glucose -> glucose 6 P
Definition
hexokinase or glucokinase

hexokinase - all tissues, small Km
glucokinase - only liver, pancreatic beta cell, large Km
Term
activates PFK-1
Definition
fructose 2,6 bis-P, product of PFK-2 on fructose 6P
Term
PEP -> pyruvate
Definition
pyruvate kinase
Term
second most common genetic deficiency causing hemolytic anemia

2 distinguishing features?
Definition
pyruvate kinase deficiency

-no Heinz bodies
-increased 2,3 DPG (lower than normal oxygen affinity)
Term
pyruvate + NADH -> lactate + NAD
Definition
lactate dehydrogenase

important in anaerobic glycolysis to reoxidize NADH
Term
pyruvate + CoA + NAD -> acetyl CoA + CO2+ NADH
Definition
pyruvate dehydrogenase

requires cofactors (thiamine, lipoic acid, CoA, FAD, NAD)
Term
cause of neonatal type I diabetes
Definition
glucokinase deficiency in newborn

pancreatic B cells cannot detect glucose and do not secrete insulin
Term
glycolysis intermediate used in trigylceride synthesis
Definition
DHAP -> glycerol 3P -> triglyceride backbone
Term
galactosemia (mild)
Definition
galactokinase deficiency

sx: cataracts early in life, galactitol trapped in lens causes swelling and cataracts
Term
galactosemia (severe)
Definition
galactose 1P uridyltransferase deficiency

more severe because galactose 1P accumulates in liver, brain, etc

sx: cataracts early in life
vomiting, diarrhea following lactose ingestion
lethargy
mental retardation
liver damage, hyperbilirubinemia
Term
fructosuria
Definition
fructokinase deficiency

benign
Term
fructose intolerance
Definition
aldolase B deficiency, autosomal recessive

sx: lethargy, vomiting
liver damage, hyperbilirubinemia
hypoglycemia, hyperuricemia
kidney disease
Term
RDS TCA cycle
Definition
isocitrate dehydrogenase

activated by ADP
inhibited by NADH, ATP
no hormonal control
Term
location: glycolysis
Definition
cytoplasm
Term
location: TCA cycle
Definition
mitochondria
Term
purpose: TCA cycle
Definition
oxidize acetyl CoA -> CO2

no net production of TCA intermediates!
Term
thiamine, lipoic acid are cofactors for these enzymes (3)
Definition
-pyruvate dehydrogenase (glycolysis)
-a-ketoglutarate dehydrogenase (TCA)
-transketolase (HMP shunt)
Term
TCA intermediates involved in other pathways:
-gluconeogenesis
-fatty acid synthesis
-heme synthesis
Definition
TCA intermediates involved in other pathways:
-malate
-citrate
-succinyl CoA
Term
location: electron transport chain
Definition
inner mitochondrial membrane

protons pumped into intermembrane space
Term
mechanism: cyanide
Definition
CN inhibits electron transport chain

antidote: nitrates to convert hemoglobin to methemoglobin, metHb binds CN avidly
Term
inhibitors of the electron transport chain
Definition
cyanide
CO
uncouplers
Term
RDS HMP shunt
Definition
glucose 6 phosphate dehydrogenase (G6PD)
Term
location: HMP shunt
Definition
cytoplasm
Term
purpose of HMP shunt
Definition
produce NADPH from abundant glucose 6 P

produce ribulose 5P for nucleotide synthesis
Term
oxidative, irreversible step in HMP shunt
Definition
glucose 6P -> NADPH and ribulose

enzyme: glucose 6P dehydrogenase
Term
nonoxidative, reversible step in HMP shunt
Definition
ribulose 5P -> ribulose 6P

enzyme: transketolases
Term
purpose of NADPH
Definition
NADPH oxidase cofactor: PMN bacteria killing

regenerates reduced glutathione: protects against ROS damage
Term
G6PD deficiency
Definition
glucose 6P dehydrogenase is RDS enzyme in HMP shunt

acute, episodic hemolytic anemia with oxidative stress (overwhelming infxn, fava beans)

x-linked recessive, heterozygote females have malaria advantage
Term
key enzymes in glycogen synthesis
Definition
glycogen synthase (RDS) (a 1,4 bonds)
branching enzyme (a 1,6 bonds)
Term
key enzymes in glycogenolysis
Definition
glycogen phosphorylase (RDS) (a 1,4 bonds)
debranching enzyme (a 1,6 bonds)
Term
von Gierke's disease
Definition
type I glycogen storage disease

glucose 6 phosphatase deficiency

sx: severe fasting hypoglycemia
high glycogen accumulation in liver leads to hepatomegaly
high blood lactate, hyperuricemia, hyperlipidemia
Term
Pompe's disease
Definition
type II glycogen storage disease
more similar to lysosomal storage diseases: inclusion bodies in lysosomes

lysosomal a 1,4 glucosidase deficiency

sx:
glycogen accumulation leads to hepatomegaly, cardiomegaly and muscle weakness
early death without tx
tx: enzyme replacement
Term
Cori's disease
Definition
type III glycogen storage disease

debranching enzyme deficency

sx: milder form of type I - mild hypoglycemia and mild hepatomegaly
normal blood lactate
Term
McArdle's disease
Definition
type V glycogen storage disease

muscle glycogen phophorylase deficiency

sx: cramps & weakness with exercise
tx: sucrose load before excercise
Term
purpose of Cori cycle
Definition
lactate becomes glucose in liver
cost of 4 ATP per cycle
Term
RDS gluconeogenesis
Definition
fructose 1,6 bisphosphatase: fructose 1,6 bis-P -> fructose 6P

activated by ATP
inhibited by AMP, fructose 2,6 bis-P
Term
pyruvate -> oxaloacetate
Definition
pyruvate carboxylase

requires biotin
mitochondrial enzyme
Term
oxaloacetate -> PEP
Definition
PEP carboxykinase

requires GTP
cytoplasmic enzyme
PEPCK expression regulated by cortisol and glucagon
Term
how does acetyl CoA regulate the fate of pyruvate?
Definition
high acetyl CoA stimulates pyruvate carboxylase (gluconeogenesis) and inhibits pyruvate dehydrogenase. high acetyl CoA occurs during fasting (due to fatty acid oxidation).
Term
how does alcoholism predispose to hypoglycemia?
Definition
NAD is converted to NADH in alcohol metabolism by alcohol dehydrogenase. high NADH diverts gluconeogenic substrates (pyruvate -> lactate, etc)
Term
mechanism: arsenic
Definition
inhibits lipoic acid, which is a cofactor for pyruvate dehydrogenase and a-ketogluterate dehydrogenase
Term
RDS fatty acid synthesis
Definition
acetyl CoA carboxylase: acetyl CoA -> malonyl CoA (eventually forms palmitate)
Term
what is the citrate shuttle?
Definition
carries acetyl CoA out of the mitochondria to cytoplasm where FA synthesis takes place
Term
sources of glycerol 3P for triglyceride synthesis
Definition
DHAP from glycolysis
Phosphorylation of free glycerol (liver only)
Term
chylomicron
Definition
triglyceride rich lipoprotein
secreted by intestinal epithelium
delivers dietary TG to periphery

Apo B-48, C and E
Term
VLDL
Definition
triglyceride rich lipoprotein
secreted by liver
delivers TG from liver to periphery

Apo B-100, C and E
Term
IDL
Definition
aka VLDL remnant

acquire cholesterol from HDL and become LDL
Term
LDL
Definition
"bad (Lousy) cholesterol"

delivers cholesterol from liver to periphery

Apo B-100
Term
HDL
Definition
"good (Healthy) cholesterol"

reverse cholesterol transport: delivers cholesterol from periphery to liver

secreted by liver and intestine

donates Apo C and E to chylomicrons and VLDL
Term
Apo B-48
Definition
on chylomicrons, required for secretion from intestinal epithelium

48 => what you ATE
Term
Apo B-100
Definition
1. on VLDL and LDL, required for secretion from liver
2. binds LDL receptor
Term
Apo C and E
Definition
required for remnant uptake by liver

donated to chylomicrons and VLDL by HDL
Term
hyperchylomicronemia
Definition
type I familial dyslipidemia
lipoprotein lipase deficiency
high TG in the form of chylomicrons
sx: pancreatitis, hepatosplenomegaly, eruptive xanthomas, *no* increased risk of atheroscelrosis
Term
familial hypercholesterolemia
Definition
type IIa familial dyslipidemia
LD receptor deficiency
autosomal dominant
high cholesterol in the form of LDL
sx: accelerated atherosclerosis, tendon xanthomas, corneal arcus
Term
hypertriglyceridemia
Definition
type IV familial dyslipidemia
high TG in the form of VLDL
hepatic overproduction of VLDL
sx: pancreatitis
Term
abetalipoproteinemia
Definition
apo B-100 and B-48 deficiency
autosomal recessive
sx in the first few months of life:
failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness
Term
RDS cholesterol synthesis
Definition
HMG CoA reductase: HMG CoA -> mevalonate

inhibited by statins
Term
lipoprotein lipase vs hormone sensitive lipase
Definition
LPL acts on chylomicrons and VLDL to release FA in adipose tissue. stimulated by insulin (fed state).

HSL acts on adipose tissue to release FA for B oxidation. inhibited by insulin, stimulated by epi and cortisol (fasting state).
Term
Lecithin cholesterol acyltransferase (LCAT)
Definition
enables reverse trasnport of cholesterol from periphery to liver: forms cholesterol esters, which are soluble in HDL core
Term
cholesterol ester transfer protein (CETP)
Definition
mediates transfer of cholesterol pesters from HDL to IDL (forming LDL).
Term
essential fatty acids
Definition
linolenic acid
linoleic acid
Term
how do statins cause rhabdomyolysis?
Definition
one of the cholesterol synthesis intermediates can be used to synthesize coenzyme Q for the ETC.

less CoQ -> impaired mito function and ATP synthesis -> muscle cell damage
Term
Tay Sachs disease
Definition
lysosomal storage disease, AR
deficient enzyme: hexosaminidase A
accumulated substrate: ganglioside GM2
sx: death by 2yo, progressive neurodegeneration, cherry-red spot on macula, *NO* hepatosplenomegaly
Term
Gaucher's disease
Definition
lysosomal storage disease, AR
deficient enzyme: B-glucocerebrosidase
accumulated substrate: glucoserebroside
sx: *crumpled paper* macrophages, avascular necrosis of femur, hepatosplenomegaly
Term
Niemann-Pick disease
Definition
lysosomal storage disease, AR
deficient enzyme: sphingomyelinase
accumulated substrate: sphingomyelin
sx: progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foamy macrophages
Term
RDS urea cycle
Definition
carbamoyl phosphate synthetase I:
NH4+ + CO2 -> caramoyl phosphate

cost: 2ATP
Term
purpose of urea cycle
Definition
convert excess nitrogen (NH4+) to urea for excretion by kidneys
Term
location: urea cycle
Definition
mitochondria and cytoplasm of liver
Term
lab values that suggest urea cycle defect
Definition
high ammonium
high glutamine
low urea (low BUN)
Term
most common urea cycle disorder
Definition
ornithine transcarbamoylase deficiency
Term
carbamoyl phosphate synthetase deficiency vs. ornithine transcarbamoylase deficiency
Definition
uracil and orotic acid elevated in ornithine transcarbamoylase deficiency

OTC deficiency is x-linked recessive, CPS deficiency is AR

both are mitochondrial enzymes in urea cycle,
cause high ammonium, high glutamine, low urea,
sx: cerebral edema, lethargy, seizures, coma, death in neonate 24 hours after birth
Term
ketogenic amino acids
Definition
leucine, lysine

can make ketone bodies in severe fasting
Term
ketogenic & glucogenic AA
Definition
isoleucine, threonine, tyrosine, tryptophan, phenylalanine

feed gluconeogenesis in severe fasting
Term
phenylketonuria
Definition
phenylalanie hydrozylase deficiency
autosomal recessive

sx: MR, growth retardation, seizures, *musty* body odor
tx: limit dietary phenylalanine, tyrosine becomes essential, monitor in pregnancy

*Nutrasweet (aspartame) contains phenylalanine
Term
Alkaptonuria
Definition
homogentisic acid oxidase deficiency
autosomal recessive

sx: ochronosis, arthritis
tx: *symptomatic* only, benign disease
Term
Homocystinuria

*increased risk of?*
Definition
cystathionine synthase deficiency or
homocysteine methyltransferease deficiency
autosomal recessive

sx: mental retardation, osteoporosis, tall stature (Marfanoid), kyphosis, lens subluxation, atherosclerosis (*stroke and MI*)
tx: for cystathionine synthase deficiency, use homocysteine methyltransferease to degrade homocysteine to methionine: decrease methionine and increase cysteine + B12 intake
*cysteine becomes essential
Term
Cystinuria

*tx*
Definition
renal proximal tubular AA transporter defect

cystine = 2 cysteines linked by disulfide bond

sx: cystine kidney stones
tx: *acetazolamide* to alkalinize the urine
Term
Maple syrup urine disease
Definition
branched chain ketoacid dehydrogenase deficiency

sx: days old infant becomes lethargic, CNS defects/MR/death if untreated
tx: limit dietary isoleucine, leucine, valine (I Love Vermont)
Term
Hartnup disease
Definition
renal neutral AA transporter defect, *tryptophan* excretion in urine

sx: pellagra (niacin is derived from tryptophan)
Term
RDS heme synthesis
Definition
delta-aminolevulinate synthetase:
glycine + succinyl CoA -> delta-aminolevulinic acid

requires *vitamin B6*
inhibited by heme
Term
Acute intermittent porphyria
Definition
urobilinogen-1 synthase deficiency (heme synthesis)
autosomal dominant but late onset and variable expression

pain in abdomen
polyneuropathy
psych*
pink urine
precipitated by drugs (*barbituates*, OCP, sulfa drugs)
Term
Other porphyrias
Definition
defect in other heme synthesis enzymes

cutaneous: photosensitivity, blistering
Term
Lead poisoning
Definition
inhibits heme synthesis: ALA dehydrase, ferrochelatase

sx: microcytosis, basophilic stipling, ringed sideroblasts, lead lines in gums and epiphyses
Term
Heme metabolism pathway: heme ->
Definition
biliverdin
bilirubin
conjugated bilirubin (in liver)
urobilinogen (in intestine, by bacteria)
stercobilin (feces) or urobilin (urine)
Term
Crigler-Najjar syndrome
Definition
UDP glucuronyl transferase deficiency
Term
Gilbert syndrome
Definition
UDP glucuronyl transferase deficiency
Term
amination of uracil =
Definition
cytosine
Term
methylation of uracil =
Definition
thymine
Term
important purine and pyrimidine precursors
Definition
purine: IMP
pyrimidine: orotic acid, UMP
Term
RDS de novo purine synthesis
Definition
glutamine PRPP amidotransferase
Term
RDS de novo pyrimidine synthesis
Definition
carbamoyl phosphate synthetase II:
glutamine + CO2 -> carbamoyl phosphate

*note: carbamoyl phosphate also a urea cycle intermidate
Term
Adenosine deaminase deficiency
Definition
purine salvage deficiency, major cause of SCID

high levels of dATP inhibit synthesis of other DNA precursors -> B and T cell dysfunction
Term
Lesch-Nyhan syndrome
Definition
absent HGPRT, defective purine salvage
X-linked recessive

sx: unrecovered purines are degraded to uric acid -> hyperuricemia, gout, *self-mutilation*, aggression
Term
orotic aciduria
Definition
defect in de novo pyrimidine synthesis: cannot convert orotic acid to UMP
autosomal recessive

sx: days old infant with orotic acid in urine (but not hyperammonemia as in OTC deficiency - urea cycle defect), megaloblastic anemia that does not resolve with B12 or folate, failure to thrive
tx: oral uridine (salvaged to UMP)
Term
antineoplastic drugs that inhibit enzymes in pyrimidine de novo synthesis (3)
Definition
hydroxyurea - ribonucleotide reductase

5-fluorouracil - thymidylate synthase

methotrexate - dihydrofolate reductase
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