Enzymes and Biochem principles Flashcards
UDP-glucuronyl transferase
conjugates bilirubin by adding glucuronyl group
- mild decrease = Gilbert
- absent = Crigler-Najjar Type 1
- mutated = Crigler-Najjar Type 2
Rate limiting step in pyrimidine synthesis is catalyzed by which enzyme
Carbamoyl phosphate synthetase II
-converts glutamine + CO2 + ATP into carbamoyl phosphate
Autosomal recessive defect in UMP synthase
Orotic aciduria
FTT, developmental delay, megaloblastic anemia that doesn’t respond to folate or B12
- no high ammonia
- orotic acid in urine
- tx with uridine monophosphate supplementation
Rxn catalyzed by UMP synthase
orotic acid –> UMP
-needed or pyrimidine synthesis
Disease resulting from absent HGPRT
Lesch-Nyhan
- X-linked
- excess uric acid production
- intellectual disability, hyperuricemia (orange “sand” in diaper), gout, dystonia, aggression, self-mutilation
- tx = allopurinol or febuxostat for gout
Rxns catalyzed by HGPRT
hypoxanthine –> IMP, guanine –> GMP
-purine salvage pathway
Rxn catalyzed by Adenosine deaminase
degradation of adenosine and deoxyadenosine in purine salvage pathway
Result of a deficiency in ADA
SCID - autosomal recessive
-due to increase in dATP which is toxic to lymphocytes
Rate limiting step in purine synthesis is catalyzed by which enzyme
Glutamine PRPP amidotransferase
PRPP –> IMP
Disease due to defect in mismatch repair
Lynch syndrome (HNPCC)
Disease due to defect in nonhomologous end joining
ataxia telangiectasia (also fanconi anemia)
Disease due to defect in nucleotide excision repair
Xeroderma pigmentosum (can’t fix thymidine dimers - very sensitive to sun)
Function of DNA pol alpha
synthesize lagging strand and make RNA primers
Function of DNA pol delta
synthesize leading strand
Function of DNA pol gamma
synthesize mitochondrial DNA
Function of DNA pol beta
base excision repair
Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
Prader-Willi syndrome
Defect in Prader-Willi syndrome
paternal gene on chromosome 15 is mutated/deleted; maternal gene is imprinted normally
POP - paternal, obesity/over eating, prader-willi
inappropriate laughter, seizures, ataxia, severe intellectual disability
Angelman syndrome
Defect in Angelman syndrome
maternal gene on chromosome 15 is mutated/deleted (paternal is imprinted)
- think “angel’s miss their mom”
- MAMA = angelMan, ataxia, maternal gene, mood change (very happy/laughing)
Enzyme that converts glucose to G-6-P
glucokinase - liver, beta cells of pancreas
hexokinase - all other tissues
Rate limiting enzyme in glycolysis
phosphofructokinase-1 (PFK-1)
converts Fructose-6-phosphate to Fructose-1,6-bisphosphate
What substrates promote PFK-1?
AMP, Fructose-2,6-bisphosphate
What substrates inhibit PFK-1?
ATP, citrate
What are the two enzymes that control production of F-2,6-BP (either decrease or increase its production)?
PFK-2 makes Fructose-2,6-BP (induced by insulin to increase glycolysis)
Fructose bisphosphatase-2 converts F-2,6-BP back to F-6-P (induced by glucagon under fasted states in order to promote gluconeogenesis)
What is the most common glycolytic enzyme deficiency?
pyruvate kinase deficiency
What is the clinical consequence of a pyruvate kinase deficiency?
hemolytic anemia
What enzyme is missing in muscle cells to prevent them from doing gluconeogenesis?
glucose-6-phosphatase
gluconeogenesis occurs in liver mostly (some in kidney and intestinal epithelium)
What are the sources for gluconeogenesis?
odd chain fatty acids, TCA molecules, AA
What is the rate limiting step in gluconeogenesis?
fructose-1,6-bisphosphatase
converts fructose-1,6-bisphosphate to fructose-6-phosphate
What promotes and what inhibits fructose-1,6-bisphosphatase?
promotes = citrate (means high energy state) inhibits = fructose-2,6-bisphosphate
What are the four irreversible enzymes of gluconeogenesis?
pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, glucose-6-phosphatase
How do epinephrine and glucagon raise blood sugar?
stimulate protein kinase A in the liver to activate glycogen phosphorylase kinase –> release glucose from glycogen
How does insulin increase glycogen formation?
activated glycogen synthase
What is the rate limiting step in glycogenesis?
Glycogen synthase - forms the alpha-1,4 glycosidic linkages
What enzyme is not found in muscles and is found in liver and acts to release glucose after glycogenolysis?
glucose-6-phosphatase
-reason glucose stored by muscles cell stays in that cell
Rate limiting enzyme in glycogenolysis
glycogen phosphorylase
Deficient enzyme in Von Gierke disease
Glucose-6-phosphatase
Deficient enzyme in Cori disease
debranching alpha-1,6-glucosidase
Deficient enzyme in Pompe disease
lysosomal alpha-1,4-glucosidase
Deficient enzyme in McArdle disease
skeletal muscle glycogen phosphorylase
Presents with lactic acidosis, hyperlipidemia, hyperuricemia (gout)
Von Gierke
Presents with cardiomegaly
Pompe disease (infantile type)
Presents with diaphragm weakness leading to resp. failure
Pompe disease
Presents with increased glycogen in liver, severe fasting hypoglycemia
Von Gierke
Presents with hepatosplenomegaly, hypoglycemia, hyperlipidemia (normal kidneys, lactate, uric acid)
Cori disease
Presents with painful muscle cramps, myoglobinuria with strenuous exercise which can lead to renal failure
McArdle disease
Severe hepatosplenomegaly, enlarged kidneys
Von Gierke disease
Tx for Von Gierke disease
frequent oral glucose and cornstarch
Which glycogen storage disease is most lethal?
Pompe disease, infantile type
Which glycogen storage disease can lead to seizures if untreated?
Von Gierke disease - due to high lactic acid
Possible products of pyruvate
oxaloacetate (gluconeogenesis), alanine (carries nitrogen), lactate (anaerobic glycolysis), acetyl-CoA (glycolysis)
Two main nitrogen transporters in the blood
alanine, glutamine
Major regulatory enzymes in TCA cycle
alpha-ketoglutarate dehydrogenase, citrate synthase, isocitrate dehydrogenase
Rate limiting step in TCA
isocitrate dehydrogenase
What are the mitochondrial uncouplers?
aspirin OD, 2,4-dinitrophenol, thermogenin in brown fat
What are the cofactors required by pyruvate dehydrogenase complex (links glycolysis to TCA cycle by converting pyruvate to acetyl-CoA)?
TLC for Nobody
- Thiamine pyrophosphate (Vit B1)
- Lipoic acid
- CoA (Vit B5, pantothenic acid)
- FAD (Vit B2, riboflavin)
- NAd (Vit B3, niacin)
What toxin causes GI distress + garlic breath and inhibits pyruvate dehydrogenase?
arsenic
What are the effects a deficiency in pyruvate dehydrogenase?
pyruvate gets shunted to lactate and alanine
- lactate acidosis, neuro defects, increase serum alanine
- tx = increase fat in diet, supplement with lycine and leucine to be used for energy instead of glucose
- can be X-linked, due to arsenic, or Vit B def.
Rate limiting enzyme in Pentose Phosphate Pathway
Glucose-6-phosphate dehydrogenase
converts G-6-P to Ribulose-5-P and NADPH
*important for forming NADPH
Purpose of PPP/HMP shunt
form NADPH for reductive reactions
How does G6PD deficiency presents?
hemolytic anemia - RBCs are unable to reduce oxidative species due to decrease in NADPH
-usually sets in after stressing factor = infection, fava beans, TB drugs, sulfonamides, nitrofurantoin
What are the two distinct cell types seen in hemolytic anemia with G6PD def?
bite cells, heinz bodies (denatured Hb precipitates within cells)
Presents with failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability
Classic galactosemia
tx - exclude galactose, lactose from diet
Deficiency in classic galactosemia
galactose-1-phosphate uridyltransferase
Presents with galactosemia and galactosuria, infantile cataracts
Galactokinase deficiency
Presents with hypoglycemia, jaundice, cirrhosis, vomiting, urine dipstick is negative for sugar
Fructose intolerance - severe hypoglycemia because the Fructose-1-P accumulates and there is no phosphate for glycogenolysis or gluconeogenesis
Tx - decrease intake of fructose and sucrose
*dipstick cannot pick up fructose
What is the deficiency in fructose intolerance?
aldolase B
-aldolase B means this is the bad fructose dz
What is the deficiency in essential fructosuria?
fructokinase
-kinase is the kind disease
Benign dz that presents with fructose in blood and urine
Essential fructosuria
What disease results from protein malnutrition?
Kwashiokor
How does kwashiokor present?
FLAMES - fatty liver, anemia, malnutrition, edema, skin lesions (child in Africa with swollen belly)
What disease results from total calorie malnutrition and causes muscle wasting, loss of subcutaneous fat, and edema?
Marasmus
What is the rate-limiting enzyme in ketone body synthesis?
HMG CoA synthase
What occurs in refeeding syndrome?
cells reuptake lytes –> drop in serum mag, phosphate, potassium
-can lead to arrhythmias and neuro problems
What leads a fruity odor on the breath?
conversion of acetoacetate to acetate in someone who is producing ketone bodies
What ketone body is detected on urine test?
acetoacetate (not Beta-hydroxybutyrate)
What occurs in starvation and DKA to cause ketone synthesis?
depletion of oxaloacetate depleted for gluconeogenesis –> build up acetyl-CoA more than TCA cycle can handle
-results in glucose and FFA shunted to ketone synthesis
What occurs in alcoholism to cause ketone synthesis?
excess NADH (low NAD+) shunts oxaloacetate to malate –> build up acetyl-CoA more than TCA cycle can handle
-results in glucose and FFA shunted to ketone synthesis
What are the fuels used during fasting states?
glucose (glycogenolysis and gluconeogenesis), FA from fat
-glucose is used by all tissues
What are the fuels made/used after fasting for 24 hours?
glucose and FA produced
- brain uses glucose
- muscles/other tissues use mostly FA, some glucose
What are the fuels made/used after fasting for 48 hours?
glucose, FA, ketone bodies produced
- brain uses mostly glucose, some ketones
- muscles/other tissues use mostly FA, some ketones
What are the fuels made/used after fasting for 5 days?
glucose, FA, ketone bodies produced
- brain uses mainly ketone bodies
- muscles/other tissues mainly use FA, some ketones
after 3 days, 60% of energy comes from ketones
Apolipoprotein that activates LCAT
ApoA-I
Apolipoprotein that mediates chylomicron secretion
ApoB-48
Apolipoprotein that mediates VLDL secretion and allows particles to leave the liver
ApoB-100
Apolipoprotein that mediates remnant particle uptake
ApoE
Apolipoprotein that acts as a cofactor for lipoprotein lipase
ApoC-II
Autosomal recessive mutation in MTP gene, presents with decrease ApoB-48 and ApoB-100, steatorrhea, night blindness and ataxia (due to decrease uptake of fat soluble vitamins)
Abetalipoproteinemia
Key cells seen on a peripheral smear of a pt with abetalipoproteinemia
acanthocytosis of RBCs (defect in cell membrane)
Functions to deliver dietary TGs to peripheral tissues and delivers cholesterol back to liver
chylomicron
Functions to deliver hepatic TGs to peripheral tissues
VLDL
Degradation product of VLDL, delivers TGs and cholesterol to liver
IDL
Delivers hepatic cholesterol to peripheral tissues, take up via receptor-mediated endocytosis
LDL
Deficiency in familial hypercholesterolemia
LDL receptor deficiency
Mediates reverse cholesterol transport from periphery to liver, repository for ApoC and ApoE
HDL
Presents with pancreatitis, hepatosplenomegaly, pruritic xanthomas, but no increased risk for arthersclerosis
high TGs, chylomicrons, cholesterol
Type I Hyperchylomicronemia
Defect in Type I hyperchylomicronemia
lipoprotein lipase or apolipoprotein C-II deficiency
Defect in Type IIa Familial hypercholesterolemia
absent or defective LDL receptors
Presents with high LDL cholesterol, can present with an MI in a very young person (before 20), tendon xanthomas (achilles typically), increased risk or atherosclerosis
Familial hypercholesterolemia
Presents with high TGs (>1000), acute pancreatitis
Hypertrigyceridemia - hepatic overproduction of VLDL
Rate limiting enzyme for fatty acid synthesis
Acetyl-CoA carboxylase (occurs in cytoplasm)
Rate limiting enzyme for Beta-oxidation of fatty acids
carnitine acetyltransferase I (occurs in mitochondria)
Rate limiting enzyme for cholesterol synthesis
HMG CoA reductase
What compounds can be made from phenylalanine?
tyrosine, dopa, dopamine, NE, Epi
What is the precursor to melanin?
dopa
What enzyme converts dopamine to NE and what cofactor does it need?
dopa beta-hydroxylase
cofactor = Vit C
What cofactor helps convert NE to Epi?
SAM (also uses cortisol)
What compounds can be made from arginine?
creatine, urea, nitric oxide
What compounds can be made from glutamate?
GABA (requires B6), Glutathione
What compounds can be made from glycine?
porphyrin (need B6) –> heme
What compounds can be made from histadine?
histamine (need B6)
What compounds can be made from tryptophan?
niacin (requires B6, B2) –> NAD/NADP
serotonin (requires BH4, B6) –> melatonin
Essential Amino Acids
PVT TIM HaLL - phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histadine, lysine, leucine
Acidic Amino Acids
Aspartate, Glutamate (negative charge at body pH)
Basic Amino Acids
Arginine, Lysine, Histadine
Amino acids that are present in histones
lysine, arginine
Amino acids needed during growth
arginine, histadine
Rate limiting enzyme in urea cycle
carbamoyl phosphate synthetase I
- converts CO2 + NH3 (ammonia) to carbmoyl phosphate
- found in mitochondria
Presents with increased orotic acid in urine and blood, decreased BUN, symptoms of hyperammonemia, presents in first few days of life
Ornithine transcarbamylase deficiency
- normally converts ornithine –> citrulline for elimination of ammonia
- tx = limit protein in diet
Tremor, slurring speech, somnolence/lethargy, vomiting, cerebral edema, blurring vision
hyperammonia - due to defect in urea cycle or liver disease
Presents with dermatitis, dementia, and diarrhea but not due to deficient Vit B3
Hartnup disease
Deficiency in Hartnup disease
deficiency in neutral amino acid transporters in the proximal tubule and on enterocytes –> decrease tryptophan for conversion to niacin –> pellegra results
Presents with vomiting, poor feeding, urine smells sweet; can lead to CNS defects, intellectual disability, death
Maple syrup urine disease
Deficiency in maple syrup urine disease
decreased branched-chain alpha-ketoacid dehydrogenase –> blocked degradation of branched amino acids (leucine, isoleucine, valine)
-tx = restrict branched chain amino acids
Presents with intellectual disability, growth retardation, seizures, fair skin, eczema, and musty body odor if untreated
Phenylketonuria (PKU)
Deficiency in PKU
decrease in phenylalanine hydroxylase or decrease in BH4 (tetrahydrobiopterin) –> can’t make tyrosine from phenylalanine
- tx with decrease phenylalanine (aspartate, meat, dairy), increase tyrosine
- causes build up phenylketones –> in urine
Presents with recurrent cystine hexagonal kidney stones
Cystinuria
Defect in cystinuria
defect in renal PCT and interstitial AA transporter that prevents reabsorption of COLA - cysteine, ornithine, lysine, arginine
tx = acetazolamide to alkalinize the urine
Presents with increased homocysteine in the urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, atherosclerosis
Homocystinuria
Defect in homocystinuria
Cystathionine synthase deficiency, or
decreased affinity of cystathionine synthase for pyridoxal phosphate (B6), or methionine synthase
Tx = pyridoxine (Vit B6) supplements or decrease methionine intake
Presents with bluish-black connective tissue (skin) and sclera (onchronosis), urine turns black on prolonged exposure to air, arthalgias
Alkaptonuria
Defect in alkaptonuria
deficiency in homogentisate oxidase –> can’t break down tyrosine –> homogentistic acid builds up in tissues
benign
Defect in albinism
decreased tyrosinase activity or defected tyrosine transport –> can’t make melanin
Cherry red spot on macula, lysosomes with onion skin, progressive neurodegeneration
Tay-Sachs disease
deficiency in hexosaminidase A - accumulate GM2 ganglioside
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Krabbe disease
deficiency of galactocerebrosidase - build up galactocerebrosidase
Central and peripheral demyelination, with ataxia and dementia, vision loss
Metachromatic leukodystrophy
deficiency of arylsulfatase A - cerebroside sulfate
Progressive neurodegeneration (dysphagia, dysarthria, ataxia), hepatosplenomegaly, foam cells, cherry spot on macula
Niemann-Pick disaese
deficiency of sphingomyelinase- build up sphingomyelin
Hepatosplenomegaly, pancytopenia, osteoporosis, lipid-laden macrophages that resemble crumpled tissue paper
Gaucher disease
deficiency in glucocerebrosidase - build up glucocerebroside
Triad of episodic peripheral neuropathy, angiokeratomas (little papules around buttock/groin), hypohidrosis
-later leads to renal failure and CV dz
Fabry disease (X-linked)
alpha-galactosidase A - build up ceramide trihexoside
Developmental delay, gargoylism (course facial features and short statures), corneal clouding, hepatosplenomegaly
Hurler syndrome
alpha-L-iduronidase deficiency
Mild Hurler syndrome + aggressive behavior, without corneal clouding
Hunter syndrome (X-linked)
iduronate sulfatase
