Biochemistry First Aid- Metabolism Part 2 (107-118) Flashcards
galactokinase deficiency is fairly mild, but what symptoms may occur?
may initially present as failure to track objects or to show social smile; galactose in blood and urine, infantile cataracts
classic galactosemia results from what enzyme deficiency
galactose-1-phosphate uridyltransferase
what are the symptoms of galactosemia
failure to thrive, infantile cataracts (galacticol accumulates in the lens of the eye), jaundice, hepatomegaly, intellectual disability
what’s the treatment for classic galactosemia
exclude galactose and lactose (galactose + glucose) from diet
what microbiologic complication can arise in patients with classic galactosemia
E. coli neonatal sepsis
_______ is converted to sorbitol via ___________
glucose is converted to sorbitol via aldose reductase
sorbitol is converted to ___________ via __________
sorbitol is converted to fructose via sorbitol dehydrogenase
what tissues have insufficient sorbitol dehydrogenase leading to risk of disease in hyperglycemic states
schwann cells (peripheral neuropathy), retina, kidney, lens
in addition to converting glucose to sorbitol, aldose reductase also converts galactose to ___________
galacticol
lactose intolerance is caused by deficiency of what enzyme
lactase
what are the three kinds of lactase deficiency
primary (loss of lactase persistence allele as an adult), secondary (loss of brush border due to gastroenteritis), congenital (defective gene from birth)
what would be the stool and breath test findings in someone with lactase deficiency
stool has low pH, breath test shows high hydrogen content with lactose tolerance test
what are the symptoms of lactase deficiency and how is it treated
Sx: flatulence, bloating, cramping, osmotic diarrhea
Tx: avoid dairy, lactase pills, lactose-free milk
what enantiomer of amino acids are found in proteins
L-form
name the essential amino acids and separate them by glucogenic, glucogenic/ketogenic, and ketogenic
glucogenic: methionine, valine, histidine
both: isoleucine, phenylalanine, threonine, tryptophan
ketogenic: leucine and lysine
name the acidic amino acids
aspartic acid and glutamic acid
name the basic amino acids and specify which is most basic
arginine, lysine, histidine
arginine is most basic
which basic amino acid has no charge at body pH
histidine
which amino acids are required during periods of growth
arginine and histidine
which amino acids are predominant in histones
arginine and lysine
which enzyme converts NH3 and CO2 to carbamoyl phosphate in the urea cycle
carbamoyl phosphate synthetase I
name the intermediates of the urea cycle (starting with aspartate entry into the cycle)
aspartate –> argininosuccinate –> arginine –> ornithine + carbamoyl phosphate –> citrulline
how is ammonia from amino acids sent off from the muscle
step 1: ammonia from amino acids gets transferred to alpha-ketoglutarate to make glutamate (generating alpha keto acids in the process);
step2: glutamate transfers ammonia to pyruvate to make alanine (regenerating alpha-ketoglutarate in the process)
explain the alanine cycle
function: the alanine cycle transports ammonia between muscle and liver;
1. alanine in muscle carries NH3 to liver,
2. alanine gets converted to pyruvate, which becomes glucose
3. glucose moves back to muscle
4. glucose gets converted to pyruvate
5. in the muscle pyruvate is aminated to form alanine
explain the Cori cycle
function: Cori cycle transports lactate to liver where it can be converted to glucose and sent back to muscle
1. in muscle glucose becomes pyruvate, then lactate
2. lactate moves from muscle to liver
3. in liver lactate becomes pyruvate, then glucose
4. glucose moves from liver back to muscle
how is ammonia disposed of in the liver
aminated alanine transfers NH3 to alpha-ketoglutarate to form glutamate;
glutamate is converted to urea to be excreted
name the two general etiologies of hyperammonemia
- acquired (liver disease)
2. hereditary (urea cycle enzyme deficiencies)
how does hyperammonemia affect metabolism
too much NH4+ depletes alpha-ketoglutarate, leading to inhibition of the TCA cycle
what are the symptoms of ammonia intoxication
tremor (asterixis), somnolence, slurred speech, vomiting, cerebral edema, blurring of vision
what is the treatment for hyperammonemia
- limit protein in diet;
- benzoate or phenylbutyrate (bind amino acid and lead to excretion) can be given to lower ammonia levels
- lactulose to acidify the GI tract and trap NH4+ for excretion
what is the role of N-acetylglutamate
N-acetylglutamate is the cofactor required by carbamoyl phosphate synthetase I
what is caused by N-acetylglutamate deficiency
hyperammonemia
how do you differentiate between N-acetylglutamate deficiency and carbamoyl phosphate synthetase I deficiency
check urea cycle enzymes; both deficiencies will cause increased ornithine, but urea cycle enzymes will be normal in N-acetylglutamate deficiency (since only the cofactor is deficient)
what is the most common urea cycle disorder and what’s its inheritance pattern
ornithine transcarbamylase deficiency;
X-linked recessive
levels of what molecule are markedly elevated in OTC deficiency (besides ornithine)
orotic acid (carbamoyl phosphate is converted to orotic acid in pyrimidine synthesis pathway)
describe the findings of OTC deficiency and explain how you would differentiate from orotic aciduria
OTC deficiency: increased orotic acid in blood and urine, decreased BUN, symptoms of hyperammonemia
like orotic aciduria, OTC deficiency shows increased orotic acid in blood and urine
unlike orotic aciduria, OTC deficiency shows hyperammonemia and DOES NOT involve megaloblastic anemia
which amino acid gives rise to tyrosine and list the derivatives of tyrosine
phenylalanine gives rise to tyrosine which can become thyroxine or dopa; dopa can become melanin or dopamine; dopamine becomes NE, which gets converted by SAM to Epi
which amino acid becomes either niacin or serotonin
tryptophan
what is the precursor for melatonin
serotonin
histamine is converted to ________ by vitamin ____
histamine is converted to histidine by vitamin B6
glycine is converted to _______ by vitamin B6
porphyrin
phorphyrin is converted to _______
heme
glutamate becomes _______ and ________
GABA and glutathione
what three molecules does arginine get converted to
creatinine, nitric oxide and urea
what is the enzyme deficiency in phenylketonuria (PKU) and what does this enzyme do
decreased phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine
(or decreased tetrahydrobiopterin cofactor in the case of malignant PKU)
what are the findings associated with PKU
intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor, excess phenylketones in urine
how is PKU treated
decreased phenylalanine and increased tyrosine in diet
describe maternal PKU
how is it caused, what happens to baby
if a pregnant woman with PKU fails to maintain a proper diet high phenylketones in the intrauterine environment can cause the baby to have intellectual disability, growth retardation, microcephaly and congenital heart defects
what is the inheritance pattern of PKU
autosomal recessive
when are babies screened for PKU and why
2-3 days after birth (not immediately because you must wait for maternal enzymes to disappear)
name three phenylketones
phenylacetate, phenylpyruvate, phenyllactate
why do patients with PKU have a musty body odor
phenylketones are aromatic compounds
why must patients with PKU avoid splenda
aspartame contains phenylalanine
what enzyme deficiency causes alkaptonuria and what does enzyme do
homogentisate oxidase catalyzes conversion of homogentisate (derived from tyrosine) to maleylacetoacetic acid, which goes on to become fumarate
is alkaptonuria a severe or benign disease
benign
what are the findings of alkaptonuria
dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air, debilitating arthralgias (because homogentisic acid is toxic to cartilage)
what are the three different causes of homocystinuria and how are they each treated
- cystathionine synthase deficiency (Tx= low methionine, high cysteine, high B12 and high folate in diet)
- low affinity of cystathionine synthase for pyridoxal phosphate (Tx= high B6 and cysteine in diet)
- homocysteine methyltransferase deficiency (Tx=high methionine in diet)
what are the findings of homocystinuria
high homocysteine in urine, intellectual disability, osteoporosis, tall stature, kyphosis, lens subluxation (down and inward) thrombosis and atherosclerosis (CVA and MI)
what causes cystinuria
hereditary defect of renal PCT and intestinal amino acid transporter for Cysteine, Ornithine, Lysine and Arginine (“COLA”)
what test is used to diagnose cystinuria
urinary cyanide-nitroprusside test
what complication can result for cystinuria
precipitation of hexagonal cystine stones
what is the difference between cystine and cysteine
cystine consists of 2 cysteines connected by a disulfide bond
what is the enzyme deficiency that causes maple syrup urine disease and what does it do
low alpha-ketoacid dehydrogenase, which normally degrades branched amino acids (isoleucine, leucine and valine), riding the blood of alpha-ketoacids
what are the symptoms of maple syrup urine disease
severe CNS defects, intellectual disability, death, urine that smells like maple syrup
how is maple syrup urine disease treated
low valine, isoleucine and leucine in diet
thiamine supplementation
what vitamin catalyzes breakdown of alpha-ketoacids by alpha-ketoacid dehydrogenase
B1
what kinds of bonds do branches vs. linkages have in glycogen
branches have alpha-1,6 bonds
linkages have alpha-1,4 bonds
describe the pathway of glycogen to G-6-P in muscle during exercise (include enzymes)
glycogen –> G-1-P (catalyzed by glycogen phosphorylase) –> G-6-P
explain how glycogen phosphorylase generates limit dextrin
glycogen phosphorylase degrades glycogen until four G-1-P residues remain on the branch (this remaining strip of four residues is called limit dextrin)
what enzyme moves three G-1-P molecules off the branch (limit dextrin) onto the linkage
4-alpha-D-glucanotransferase (aka debranching enzyme)
which enzyme cleaves the last G-1-P off of the branched glycogen chain
alpha-1,6-glucosidase (a debranching enzyme)
name the four most common glycogen storage diseases
Von Gierke disease, Pompe disease, Cori disease, McArdle disease
(“Very Poor Carbohydrate Metabolism”)
what is the enzyme deficiency and what are the findings of Von Gierke disease
glucose-6-phosphatase deficiency (G-6-P to glucose)
severe fasting hypoglycemia, very high glycogen in liver, high blood lactate, hepatomegaly
how is Von Gierke disease treated
frequent oral glucose/cornstarch; avoid fructose and galactose
what is the deficient enzyme of Pompe disease and what are the findings
lysosomal alpha-1,4-glucosidase (acid maltase);
cardiomyopathy and systemic disease leading to early death
what is the enzyme deficiency of Cori disease and what are the findings
alpha-1,6-glucosidase deficiency;
milder form of Von Gierke disease with normal blood lactate, gluconeogenesis is intact
what is the enzyme deficiency in McArdle disease and what are the findings
skeletal muscle glycogen phosphorylase is deficient;
findings: increased glycogen in muscle that can’t be broken down leading to painful muscle cramps, myoglobinuria (red urine) with exercise and arrhythmia from electrolyte abnormalities
name 6 lysosomal storage diseases that are sphingolipidoses
Fabry disease, Gaucher disease, Niemann-Pick disease, Tay-Sachs disease, Krabbe disease, Metachromatic leukodystrophy
name the 2 lysosomal storage diseases that are mucopolysaccharidoses
Hurler syndrome and Hunter syndrome
which two lysosomal storage diseases are X-linked recessive as opposed to autosomal recessive
Fabry disease (a sphingolipidosis) and Hunter syndrome (a mucopolysaccharidosis)
what is the enzyme deficiency, accumulated substrate and clinical findings of Fabry disease
alpha-galactosidase A;
ceramide trihexose accumulates
findings: peripheral neuropathy, angiokeratomas (red/blue and raised skin), cardiovascular/renal disease
what is the enzyme deficiency, accumulated substrate and clinical findings of Gaucher disease
glucocerebrosidase (beta-glucosidase) deficiency;
glucocerebrosidase accumulates;
findings: hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)
what is the most common lysosomal storage disease
Gaucher disease
how is Gaucher disease treated
recombinant glucocerebrosidase
what is the enzyme deficiency, accumulated substrate and clinical findings of Niemann-Pick disease
sphingomyelinase deficiency;
sphingomyelin accumulates;
findings: progressive neurodegeneration, hepatosplenomegaly, “cherry red” spot on macula, foam cells (lipid-laden macrophages)
what is the enzyme deficiency, accumulated substrate and clinical findings of Tay-Sachs disease
hexosaminidase A deficiency;
GM2 ganglioside accumulates;
findings: progressive neurodegeneration, developmental delay, lysosomes with onion skin, “cherry red” spot on macula (like Niemann-Pick), no hepatosplenomegaly (vs. Niemann-Pick)
what is the enzyme deficiency, accumulated substrate and clinical findings of Krabbe disease
galactocerebrosidase deficiency;
galactocerebroside and psychosine accumulate;
findings: peripheral neuropathy, developmental delay, optic atrophy, globoid cells
what is the enzyme deficiency, accumulated substrate and clinical findings of metachromatic leukodystrophy
arylsulfatase A deficiency;
cerebroside sulfate accumulates;
findings: central and peripheral demyelination with ataxia, dementia
what is the enzyme deficiency, accumulated substrate and clinical findings of Hurler syndrome
alpha-L-iduronidase deficiency;
heparan sulfate and dermatan sulfate accumulate;
findings: developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
what is the enzyme deficiency, accumulated substrate and clinical findings of Hunter syndrome
iduronate sulfatase deficiency;
haparan sulfate and dermatan sulfate accumulate;
findings: same as Hurler, but milder + aggressive behavior, but no corneal clouding
what molecule is required in order to transport long chain fatty acids into mitochondrial matrix for degradation
carnitine
what are the clinical effects of carnitine deficiency
weakness, hypotonia, and hypoketotic hypoglycemia
what does the citrate shuttle do vs. the carnitine shuttle
citrate shuttle transports acetyl-CoA to the cytoplasm in the form of citrate for synthesis of fatty acids
carnitine shuttle transports acyl-CoA into mitochondria for degredation
in the liver, fatty acids and amino acids are metabolized to _________ and ________ so that they can be used by the brain and muscle
acetoacetate and beta-hydroxybutyrate
explain how starvation, DKA and alcoholism both cause overproduction of ketone bodies
in starvation and DKA oxaloacetate is depleted for gluconeogenesis, causing a build up of acetyl-CoA;
in alcoholism, excess NADH shunts oxaloacetate to acetyl-CoA;
in both cases acetyl-CoA shunts glucose and FFAs toward production of ketones
how many calories in: fat carbohydrate protein alcohol
1g of fat= 9 kcal
1g of carbohydrate= 4 kcal
1g of protein= 4 kcal
1g of alcohol= 7 kcal
of these energy sources (creatine phosphate, aerobic metabolism, anaerobic metabolism, stored ATP) list which peak at:
-0 sec, 5 sec, 30 sec, 1 hour
0 sec: stored ATP
5 sec: creatine phosphate
30 sec: anaerobic metabolism
1 hour: aerobic metabolism
during starvation how long does it take for glycogen reserves to deplete
1 day (UWorld says 12-18 hours)
which cell type cannot use ketones and why
RBCs cannot use ketones because they lack mitochondria
what processes occur during the first 3 days of starvation
depletion of glycogen reserves in liver;
release of FFA from adipocytes;
muscle and liver use FFA instead of glucose;
hepatic gluconeogenesis (uses alanine, lactate, glycerol, proprionyl CoA from odd-chain FFAs)
after day 3 of starvation what determines how quickly protein degradation and organ failure will ensue
amount of adipose stores (soon after adipose stores are depleted the body will shift to protein degradation for energy)
what is the enzyme and reaction of the rate-limiting step of cholesterol synthesis
HMG-CoA reductase converts HMG-CoA to mevalonate
what drug is a reversible competitive inhibitor of HMG-CoA reductase
statins
list the enzymes and intermediates in the pathway from VLDL in the liver to LDL in the blood
VLDL –> IDL via lipoprotein lipase
IDL –> LDL via hepatic TG lipase
what does hormone-sensitive lipase do vs. what pancreatic lipase does
hormone-sensitive lipase degrades TG stored in adipocytes
pancreatic lipase degrades dietary TGs in the small intestines
2/3 of plasma cholesterol is esterified by _______
lecithin-cholesterol acyltransferase (LCAT)
what does cholesterol ester transfer protein (CETP) do
mediates transfer of cholesterol esters from HDL to other lipoproteins (VLDL, IDL, LDL)
in which lipid particles (i.e. chylomicron, VLDL, IDL, LDL, HDL) will you find Apolipoprotein-E
chylomicron, VLDL, IDL, HDL
not LDL
in which lipid particles (i.e. chylomicron, VLDL, IDL, LDL, HDL) will you find Apolipoprotein-B100
VLDL, IDL, LDL
what does apolipoprotein-B48 do
mediates chylomicron secretion (so it is found only in chylomicrons and chylomicron remnants)
what does apolipoprotein-CII do
lipoprotein lipase cofactor
what does apolipoprotein-AI do
activates LCAT (so it is found in chylomicrons and HDL)
what are lipoproteins composed of
cholesterol, TGs, and phospholipids
which lipoproteins carry the most cholesterol
LDL and HDL
LDL transports cholesterol from where to where
LDL transports cholesterol from liver to tissues
HDL transports cholesterol from where to where
HDL transports cholesterol from tissues to liver
where do chylomicrons come from and what do they do
they’re secreted by intestinal epithelial cells and they transport TGs to tissues and cholesterol to liver in the form of chylomicrons (which are mostly depleted of their TGs)
where does VLDL come from and what does it do
secreted by liver; transports hepatic TGs to tissues
where does IDL come from and what does it do
IDL is formed via breakdown of VLDL;
it delivers TGs and cholesterol to liver
where does LDL come from and what does it do
formed from IDL via hepatic lipase;
it delivers cholesterol from liver to tissues
where does HDL come from
secreted by liver and intestines
what lipoproteins does HDL harbor and why is this important
HDL holds Apolipoproteins E and C (as well as A);
E and C are important for chylomicron and VLDL metabolism
alcohol increases synthesis of what lipoprotein (i.e. IDL, VLDL, HDL, LDL, chylomicron)
HDL
name 3 familial dyslipidemias
- type I = hyperchylomicronemia
- type IIa = familial hypercholesterolemia
- type IV = hypertriglyceridemia
what is the inheritance pattern of hyperchylomicronemia and what’s the inherited defect
autosomal recessive;
lipoprotein lipase deficiency or altered apolipoprotein-C2 (lipoprotein lipase cofactor)
what is increased in the blood in hyperchylomicronemia
chylomicrons, TG, cholesterol
what is the inheritance pattern of familial hypercholesterolemia and what is the inherited defect
autosomal dominant;
absent or defective LDL receptors
is there a difference between familial hypercholesterolemia heterozygotes and homozygotes?
yes;
although the disease is autosomal dominant expression levels vary
homozygotes: around 700+ mg/dL
heterozygotes: around 300mg/dL
what symptoms would you look for in a patient with familial hypercholesterolemia;
what fatal complication may occur
xanthomas, corneal arcus
accelerated atherosclerosis can progress to MI
what is the inheritance pattern of familial hypertriglyceridemia and what is the inherited defect
autosomal dominant;
hepatic overproduction of VLDL
what serious complication can arise from familial hypertriglyceridemia
pancreatitis
