Biochemistry Flashcards
What enzymes are effected by lead poisoning?
δ-Aminolevlinate dehydratase and ferrochelatase Results in anemia, ALA accumulation, and elevated zinc protoporphyrin levels In children, lead poisoning can cause anemia, interstitial nephritis, constipation, abdominal pain, decreased vitamin D metabolism, loss of milestones/cognitive impairement, behavioral problems, encephalopathy A/w exposure to dust/paint in homes built before 1978 Dx: blood lead levels
Orotic aciduria
Autosomal recessive defect in uridine monophosphate synthase (inability to convert orotic acid to UMP) Presents in children as megaloblastic anemia that can’t be cured with folate or vitamin 12 and failure to thrive No hyperammonemia, hypersegmented neutrophils, glossitis, orotic acid in urine Tx: uridine monophosphate to bypass mutated enzyme
Acute intermittent porphyria
Defect in porphobilinogen deaminase Characterized by abdominal pain, port wine-colored urine, polyneuropathy, psychological disturbances Tx: glucose and heme which inhibits ALAS
Porphyria cutanea tarda
Defect in uroporphyrinogen decarboxylase Characterized by blistering cutaneous photosensitivity, tea-colored urine
Sideroblastic anemia
X-linked defect in δ-aminolevulinic acid synthase Characterized by ringed sideroblasts (iron-laden macrophages), microcytic anemia
How is glutamate formed?
Transamination reaction from alpha-ketoglutarate using PLP as a cofactor. Oxidative deamination from alpha-ketoglutarate using glutamate dehydrogenase as a catalyst (requires NAD(P)H and NH3). Deamination reaction from glutamine catalyzed by glutaminase.
How is glutamine formed?
Glutamine is formed from glutamate via glutamine synthase (requires NH4+ and ATP).
How is tyrosine formed?
Tyrosine is formed from phenylalanine. Catalyzed by phenylalanine hydroxylase. Requires BH4 and O2.
How is GABA formed?
GABA is formed from a decarboxylation reaction from glutamate. Requires glutamic acid decarboxylase and PLP.
How is dopa formed?
Dopa is formed from tyrosine. Requires tyrosine hydroxylase and BH4.
How is dopamine formed?
Dopamine is formed from dopa via dopa decarboxylase and PLP.
How is norepinephrine formed?
Norepinephrine is formed from dopamine via a hydroxylation reaction. Catalyzed by dopa beta-hydroxylase. Requires O2, Cu2+, and vitamin C.
How is epinephrine formed?
Epinephrine is formed via a methylation reaction from norepinephrine. Requires SAM.
What is required to produce PLP?
Vitamin B6. B6 is inhibited by isoniazid (treatment for TB)
What is required to produce SAM?
Vitamin B12 and folate.
How is serotonin formed?
Hydroxylate and decarboxylase reactions from tryptophan. Requires BH4 and PLP.
How is histamine formed?
Histamine is formed by a decarboxylation reaction from histidine. Requires PLP.
What is cleaved by pepsin?
Pepsin cleaves the peptide bond in which the carboxyl group is contributed by aromatic amino acids (tryptophan, phenylalanine, tyrosine) and leucine Produced by chief cells in the stomach
What is cleaved by trypsin?
Trypsin cleaves peptides bonds in which the carboxyl group in contributed by arginine or lysine (basic) Endopeptidase produced by the pancreas
What is cleaved by chymotrypsin?
Chymotrypsin cleaves the peptide bond in which the carboxyl group is contributed by aromatic amino acids (tryptophan, phenylalanine, tyrosine) and leucine Endopeptidase produced by the pancreas
What is cleaved by elastase?
Elastase cleaves at the carboxyl end of amino acids with small, uncharged side chains (alanine, glycine, serine) Endopeptidase produced by the pancreas
What is cleaved by carboxypeptidase A?
Carboxypeptidase A cleaves aromatic amino acids (tryptophan, phenylalanine, tyrosine) from the C-terminal Exopeptidase produced by the pancreas
What is cleaved by carboxypeptidase B?
Carboxypeptidase B cleaves basic amino acids (arginine, lysine) from the C-terminal Exopeptidase produced by the pancreas
What is cleaved by aminopeptidase?
Aminopeptidase cleaves amino acids from the N-terminal Exopeptidase produced by enterocytes
What is sucrose?
Glucose-alpha 1, 2-fructose
What is lactose?
Galactose-beta 1,4-glucose
What is maltose?
Glucose-alpha 1, 4-glucose
What is isomaltose?
Glucose-alpha 1, 6-glucose
What are the important cofactors for transaminations?
Pyridoxal phosphate (PLP)/vitamin B6 (pyridoxine)
Vitamin B6 deficiency
Caused by poor diet or drug interaction (isoniazid for TB) Decreased synthesis of neurotransmitters, NAD, heme –> neurologic and pellagra-like symptoms and anemia (sideroblastic)
What are the sources of the two nitrogens in urea?
NH4+ (from alanine or glutamine) and aspartate
How does the body get rid of excess nitrogen?
Urea (90%), NH4+, creatinine, uric acid (from purine catabolism)
What causes build-up or orotic acid and what are the symptoms?
Inborn error of ornithine transcarbamoylase or pyrimidine synthesis pathway dysfunction (OPRT, OMPDC) Congenitally, causes lethargy, hypothermia, and respiratory alkalosis 24-48 hours after birth and later vomiting, encephalopathy, cerebral edema Causes megaloblastic anemia that isn’t cured with folate or vitamin B12 supplementation
What are the symptoms of ornithine transcarbamoylase deficiency?
Low BUN, blood arginine Undetectable blood citrulline Elevate blood ammonia, glutamine, orotic acid
How would you treat dysfunctions in the urea cycle?
Low protein diet (minimize waste nitrogen) and drugs (benzoate, phenylacetate) that eliminate waste nitrogen (conjugates and excretes glycine and glutamine)
Name transaminase pairs
α-ketoglutarate/glutarate alanine/pyruvate aspartate/oxaloacetate
What is Acute Intermittent Porphyria?
Autosomal dominant mutation of PBG deaminase Increase in urinary ALA and PBG Acute, recurrent attacks of severe abdominal pain, tachycardia, agitation, and psychiatric symptoms
What is Porphyria Cutanea Tarda?
Autosomal dominant decrease in uroporphyrinogen decarboxylase Increased urinary uroporphyrin III Chronic blistering lesions on sun-exposed areas of skin
What is Congenital Erythropoietic Porphyria?
Autosomal recessive mutation in URO III cosynthase (in bone marrow) that results in severe photomutilation and hypertrichosis (abnormal amount of hair growth)
What is the rate-limiting reaction of heme synthesis in bone marrow?
Ferrochelatase reaction
Describe the synthesis of nonessential amino acids?
Aspartate + Glutamine –> Asparagine Oxaloacetate –> Aspartate Serine –> Glycine Phosphoglycerate –> Serine Serine + Methionine –> Cysteine Pyruvate –> Alanine Phenyalanine –> Tyrosine Glutamate Glutamine
What is phenylketonuria?
Autosomal recessive defect in phenylalanine hydroxylase Results in build-up of phenylalanine and low tyrosine –> vomiting, hyperactivity, purposeless movement, athetosis, musty odor, mental retardation Treat by restricting phenylalanine in the diet
Which amino acid are branch-chained?
Valine, leucine, and isoleucine
What is Maple Syrup Urine Disease?
Autosomal recessive mutation in branched chain α-ketoacid dehydrogenase (oxidative decarboxylation) Urine smells like maple syrup Enzyme subunit E1 requires thiamine (vitmain B1); complex also requires vitamins B3 (NAD+) and B2 (riboflavin)
What is tyrosinemia?
Autosomal recessive error of tyrosine metabolism (fumarylacetoacetate hydrolase) Liver (cirrhosis, HCC) and kidney (Fanconi syndrome) distubances, mental retardation Treat with a low protein diet
What is Lesch-Nyhan Syndrome?
X-linked deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) Results in build-up of uric acid, gout, mental retardation, hypotonia, self-mutilating behavior Causes poor utilization of vitamin B12 –> megaloblastic anemia
What is albinism?
Autosomal recessive defect in tyrosinase that results in lack of production of melanin (albino vs. albinoid) Lots of eye problems
What is α-1 antitrypsin deficiency
Autosomal recessive disorder with low or no α-1 antitrypsin which inhibits neutrophil elastase Causes liver disease in children and panacinar emphysema in adults MM, MZ, ZZ genotypes
What is cystic fibrosis?
Autosomal recessive mutation in CFTR gene CFTR protein has iron conductance defect which lead to thickened fluid secretions 2/3 of cases have a deletion of phenylalanine in position 508 which causes the protein to misfold and increases degradation in the cell Diagnose with sweat test (will have more NaCl) Complications include lung diseases, nasal polyps, pancreatic insufficiency and malabsorption, liver disease
How do branched chain amino acids produce energy?
Isoleucine and leucine can produce acetyl CoA Isoleucine and valine can produce succinyl CoA
How is hyperammonemia produce neurotoxicity?
1) Excess NH3 inhibits glutaminase resulting in less glutamate to produce neurotransmitters 2) Glutamine enters mitochondria and hydrolysed to glutamate and NH3; NH3 increases pore permeability ad production of ROS 3) NH3 increases cell permeability to Ca2+ Symptoms include seizures, somnolence, apnea, coma, cerebral edema
What happens to insulin and glucagon after a high carbohydrate meal?
Insulin increases Glucagon decreases
What happens to insulin and glucagon after a high protein meal (with no or low carbs)?
Insulin increases –> increased protein synthesis in muscle Glucagon increases –> gluconeogenesis in liver
What do glucocorticoids (e.g. cortisol) do?
1) Stimulates lipolysis in adipose tissue 2) Stimulates muscle protein break-down 3) Stimulates gluconeogensis and glycogen breakdown 4) Makes tissues more sensitive to catecholamines
What are the seven amphibolic intermediates of amino acids?
Pyruvate, acetyl CoA, acetoacetate, α-ketoglutarate, succinyl CoA, fumarate, oxaloacetate
What are the ketogenic amino acids (e.g. carbons converted to acetyl CoA or acetoacetate)?
Leucine, isoleucine, lysine, phenylalanine, tryptophan, tyrosine
What is gout?
A disease characterized by hyperuricemia Uric acid causes sodium urate crystal deposition in joints Treat with NSAIDs and colchicine (acute) and allopurinol (chronic)
What are the origins of the atoms on the purine ring?
CO2, aspartate, glutamine, glycine, and 2 N10-FH4
What is Severe Combined Immunodeficiency Disease (SCID)?
Deficiency in adenosine deaminase that results in defective B and T cells
What are the origins of the atoms on the pyrimidine ring?
Glutamine, CO2, aspartate
Klinefelter Syndrome
Genotype: 47,XXY Symptoms: bi-lateral gynecomastia, decreased testicular size, body hair, increased FSH, decreased testosterone, oligospermia –> infertility, tall stature, mild learning difficulties
Hunter Syndrome
Inheritance: X-linked recessive Mechanism: defect of lysosomal enzyme α-L-iduronidase Symptoms: excretion of mucopolysaccharides
McArdle Syndrome
AR glycogen storage disease due to deficiency in skeletal muscle glycogen phosphorylase → inability to break down glycogen in muscle
Characterized by painful muscle cramps, myoglobinuria with strenuous exercise, electrolyte abnormalities → arrhythmias
Turner Syndrome
Genotype: 45,X/46,XX Symptoms: webbed neck, broad chest, widely space nipples, small, elongated ovaries –> infertility, short stature; FEMALES ONLY
Down Syndrome
Genotype: 47,XX,+21 (trisomy 21) Symptoms: mental retardation, growth retardation, epicanthic folds, simian crease, congenital heart defects, gap between first and second toes, abundant neck skin, early onset Alzheimer’s Complications: increased risk of acute megakaryoblastic leukemia
Patau Syndrome
Genotype: 47,XX,+13 (trisomy 13) Symptoms: small head, mental retardation, cleft lip and palate, cardiac defects, renal defects, rocker bottom feet, polydactyly
Edwards Syndrome
Genotype: 47,XX,+18 (trisomy 18) Symptoms: mental retardation, small jaw, low set ears, short neck, overlapping fingers, renal malformation (e.g. horseshoe kidney), rocker bottom feet, heart abnormalities
Angelman Syndrome
Mechanism: deletion of maternal 15q11-q13; imprinting on 15q13 and silencing of maternal locus Symptoms: hypotonia (low muscle tone), seizures, jerky, uncoordinated movement, mental retardation, unprovoked/inappropriate smiling or laughter, lack of speech
Huntington Disease
Inheritance: autosomal dominant Mechanism: CAG repeats in exon 1 of HTT gene (4p16.3) –> toxic gain of function Symptoms: movement disorders (sudden, jerky, involuntary movement), problems with balance and coordination, swallowing problems, dementia
Cystic Fibrosis
Mechanism: 3 bp deletion ΔF508 on CFTR gene that encodes a chloride channel Symptoms: increased NaCl in sweat, pancreatic atrophy, thick mucus in airways
Hereditary Hemochromatosis
Symptoms: iron deposition in hepatocytes cause fibrosis
Sickle Cell Anemia
Mechanism: missense mutation in hemoglobin (Glu –> Val) Symptoms: cells sickle
Marfan Syndrome
Inheritance: autosomal dominant Mechanism: defect in fibrillin (FBN1 or FBN2) Symptoms: skeletal abnormalities, ectopia lentis, cardiovascular lesions Complications: aortic disection
Fragile X Syndrome
Mechanism: CGG repeats; loss of function of the FMR1 gene Symptoms: mental retardation, long faces, large ears
Pompe Disease
AR glycogen storage disease resulting from a deficiency of the lysosomal enzyme acid maltase (α-1,4-glucosidase) → glycogen deposits accumulate in lysosomes
Results in cardiomyopathy, hypotonia
Leads to early death
Gaucher Disease
AR lysosomal storage disease caused by deficiency of glucocerebrosidase (β-glucosidase) that results in a build-up of glucocerebrosidase
Symptoms include hepatosplenomegaly, pancytopenia, aseptic necrosis of the femur, bone crises, Gaucher cells (lipid laden macrophages)
Tx: recombinant glucocerebrosidase
von Gierke Disease
AR glycogen storage disease caused by a defect in glucose-6-phosphate → cannot convert to glucose for release into the blood stream
Characterized by severe fasting hypoglycemia, increased glycogen in the liver → hepatomegaly, increased blood lactate
Tx: frequent oral glucose, avoidance of fructose and galactose
Tay-Sachs
AR lysosomal storage disease caused by a defect in hexosaminidase A causing accumulation of GM2 ganglioside
Symptoms: severe mental retardation, death before age 10, cherry-red spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick)
Niemann-Pick Disease
AR lysosomal storage disease caused by a defect in spingomyelinase causing accumulation of sphingomyelin
Characterized by progressive neurodegeneration, hepatosplenomegaly, “cherry-red” spot on macula, foam cells (lipid-laden macrophages)
DiGeorge Syndrome
Mechanism: 22q11.2 deletion Symptoms: congenital heart disease, palate defects, recurrent infections, hypocalcemia
Rett Syndrome
Mechanism: epigenic disease; mutation in the MECP2 protein that leads to expression of normally silence genes affecting brain function Symptoms: Lethal in males, neurological disorder
Myotonic Dystrophy
Mechanism: CTG repeats that alter RNA splicing Symptoms: muscle wasting, myotonia (weakness and wasting of voluntary muscles in the face, neck, and lower arms and legs), cardiac arrhythmia, cataracts
Leber Hereditary Optic Neuropathy (LHON)
Inheritance: maternally through mitochondrial DNA Mechanism: missense mutations in any of three genes encoding respiratory enzymes Symptoms: optic nerve degeneration
Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
Inheritance: maternally through mitochondrial DNA Symptoms: mictochondrial myopathy, deafness, dementia
Prader-Willi Syndrome
Mechanism: deletion of paternal 15q11-q13; imprinting Symptoms: hypotonia (low muscle tone), initial failure to thrive, mild/moderate mental retardation, hypogonadism, eating disorder (obesity)
Cori disease
AR defect in α-1,6-glucosidase (debranching enzyme) → decreased release of glucose during glycogenolysis
Milder fasting hypoglycemia, normal blood lactate levels (compared to von Gierke)
Fabry disease
X-linked recessive lysosomal storage disease caused by a defect in α-glactosidase A
Accumulation of ceramide trihexoside
Characterized by peripheral neuropathy of the hands and feet, angiokeratomas, cardiovascular/renal disease
