BR biochemistry: amino acid metabolism

1) serotonin
2) melatonin
3) niacin

1) glucogenic = degraded to pyruvate or intermediates in citric acid cycle)
2) ketogenic = degraded to acetyl CoA or acetoacetyl CoA

1) catecholamines
2) thyroid hormones
3) melanin
4) dopamine
5) degraded to homogentisate

1) leucine
2) isoleucine
3) valine
4) degraded to branched-chain α-ketoacids that can enter the citric acid cycle.

1) accepts a methyl group from methyl-folate to become S-adenosylmethionine, a common donor of a single carbon in metabolism.

1) alanine
2) cysteine
3) glycine
4) serine, threonine, and tryptophan

1) isoleucine (ketogenic and glucogenic)
2) leucine (exclusively ketogenic)

1) leucine and lysine (both exclusively ketogenic)
2) phenylalanine, tryptophan, and tyrosine (all are ketogenic and glucogenic)

1) glutamate
2) glutamine
3) histidine
4) arginine
5) proline.

1) isoleucine
2) valine
3) methionine
4) threonine.

1) phenylalanine
2) tyrosine

1) aspartate
2) asparagine.

1) phenylalanine hydroxylase
2) tetrahydrobiopterin (BH4) and oxygen

conversion of phenylalanine to tyrosine, tyrosine to dopa, and tryptophan to serotonin.

Dihydrobiopterin (BH2) is converted back into BH4 by dihydrobiopterin reductase using NADPH as a cofactor.

1) Phenylpyruvate
2) phenylacetate
3) phenyllactate

deficiency of dihydrobiopterin reductase

phenylalanine hydroxylase

1) tyrosine hydroxylase
2) BH4 and O2

1) dopamine
2) tyrosinase
3) autosomal recessive
4) albinism

tyrosine

1) Homogentisate is converted to maleylacetoacetate by homogentisate oxidase

1) alkaptonuria
2) homogentisate turns urine black

1) fumarylacetoacetate hydrolase
2) tyrosinosis
3) Symptoms:
a. lethargy
b. drowsiness
c. irritability
d. anorexia

Fumarylacetoacetate is converted to fumarate, which is a substrate in the citric acid cycle, and acetoacetate.

1) AR
2) Phenylalanine hydroxylase: catalyzes conversion of phenylalanine to tyrosine
3) Deficiency leads to increased phenylalanine and neurotoxic phenylketones and acids and decreased tyrosine levels

1) Mental retardation
2) fair skin (decreased melanin synthesis from tyrosine)
3) Mousy odor of affected individual
4) Vomiting simulating congenital pyloric stenosis

1) Must screen for phenylalanine after child is exposed to phenylalanine in breast milk
2) Treatment: restrict phenylalanine, add tyrosine, and restrict aspartame (contains phenylalanine) from diet
3) Pregnant women with PKU must restrict phenylalanine from diet to prevent neurotoxic damage to the fetus in utero

1) AR
2) BH2 reductase: cofactor for phenylalanine hydroxylase, which converts phenylalanine to tyrosine
3) Deficiency leads to increased phenylalanine and neurotoxic byproducts and decreased tyrosine and BH4 levels

1) Similar to classic PKU
2) Neurologic problems occur regardless of restricting phenylalanine intake
3) Inability to metabolize tryptophan or tyrosine (require BH4), which causes decreased synthesis of neurotransmitters (serotonin and dopamine, respectively)
3) Treatment: restrict phenylalanine in diet; administer l-dopa and 5-hydroxytryptophan to replace neurotransmitters and BH4 replacement

1) Tyrosinase: catalyzes a reaction converting tyrosine to dopa and dopa to melanin
2) melanocytes present but do not contain melanin pigment
3) AR

1) Absence of melanin in hair (white hair)
2) eyes (photophobia, nystagmus)
3) skin (pink skin with increased risk of UV light-related skin cancer)

1) AR
2) Homogentisate oxidase: catalyzes conversion of homogentisate to maleylacetoacetate
3) Deficiency leads to increased homogentisate in urine (turns black when oxidized by light)

1) Articular cartilage and sclera darken (ochronosis) due to homogentisate deposition
2) Degenerative arthritis in spine, hip, and knee

1) AR
2) Fumarylacetoacetate hydrolase: catalyzes conversion of maleylacetoacetate to fumarylacetoacetate
3) Deficiency leads to increased tyrosine levels

1) Liver damage (hepatitis progressing to cirrhosis and hepatocellular carcinoma)
2) kidneys (aminoaciduria and renal tubular acidosis)

1) AR
2) Branched-chain α-ketoacid dehydrogenase: enzyme normally present in muscle and catalyzes the second step in degradation of isoleucine, leucine, and valine
3) Deficiency leads to increased levels of branched-chain amino acids and their corresponding ketoacids in blood and urine

1) Feeding difficulties
2) vomiting
3) seizures, hypoglycemia, fatal without treatment
4) Urine has odor of maple syrup
5) Treatment: restrict intake of branched-chain amino acids to the amount required for protein synthesis

1) AR
2) Cystathionine synthase: catalyzes conversion of homocysteine plus serine into cystathionine
3) Deficiency leads to increased levels of homocysteine and methionine
4) Homocysteine damages endothelial cells, causing thrombosis and thromboembolic disease

1) Similar to Marfan syndrome: dislocated lens, arachnodactyly (spider fingers), eunuchoid features (arm span > height)
2) Distinctive features include mental retardation, vessel thrombosis (e.g., cerebral vessels), osteoporosis
3) Treatment: high doses of vitamin B6, restriction of methionine, addition of cysteine

1) AR
2) Propionyl carboxylase: catalyzes conversion of propionyl CoA to methylmalonyl CoA
3) Deficiency leads to increased levels of propionic acid and odd-chain fatty acids in the liver

1) developmental retardation
2) vomiting
3) ketosis
4) neutropenia
5) periodic thrombocytopenia
6) Treatment: low-protein diet; l-carnitine (improves β-oxidation of fatty acids); increased intake of methionine, valine, isoleucine

1) AR
2) Methylmalonyl CoA mutase: catalyzes conversion of methylmalonic acid to succinyl CoA, using vitamin B12 as a cofactor
3) Deficiency leads to increased levels of methylmalonic and propionic acids

1) failure to thrive
2) vomiting
3) dehydration
4) seizures
5) Rule out vitamin B12 deficiency as a cause
6) Treatment: low-protein diet; l-carnitine (improves β-oxidation of fatty acids); increased intake of methionine, valine, isoleucine

metabolized primarily in muscle, not liver

1) leucine (ketogenic) goes to acetyl CoA and acetoacetate
2) isoleucine (ketogenic and glucogenic) into acetyl CoA and succinyl CoA
3) valine (glucogenic) goes to succinyl CoA

by the transfer of the adenosyl group from ATP to methionine

1. After donation of its methyl group, SAM becomes S-adenosylhomocysteine.
2. The methyl group is transferred to a variety of acceptors (e.g., norepinephrine), resulting in a methylation product (e.g., epinephrine).

homocyteine

1) Homocysteine can resynthesize methionine with the aid of vitamin B12 and folate
2) Vitamin B12 removes the methyl group from N5-methyltetrahydrofolate (N5-methyl-FH4) and produces tetrahydrofolate (FH4)
3. Methylated vitamin B12 (methyl-B12) transfers the methyl group to homocysteine, which produces methionine.

1) Homocysteine combined with serine is converted to cystathionine by cystathionine synthase
Note: Deficiency of cystathionine synthase produces homocystinuria

Cystathionine, after an intermediate reaction, is converted to propionyl CoA and cysteine

degraded to propionyl CoA → methylmalonyl CoA → succinyl CoA sequence to enter the citric acid cycle

1) Epinephrine
2) methylated nucleotides
3) creatine
4) melatonin
5) phosphotidylcholine

1) tyrosine, which is converted to dopa by tyrosine hydroxylase (copper-containing rate-limiting enzyme) in the cytoplasm
2) Cu and BH4 cofactors

BH2 is converted back into BH4 by dihydrobiopterin reductase, using NADPH as a cofactor

1) dopamine by dopa decarboxylase
2) occurs in storage vesicles in the adrenal medulla and synaptic vesicles in neurons.

1) Catechol-O-methyltransferase (COMT)
2) monoamine oxidase (MAO)
3) metabolize dopamine into homovanillic acid (HVA)

1) converted to norepinephrine by dopamine hydroxylase, a copper-containing enzyme, which uses ascorbic acid as a cofactor
2) in vesicle

COMT and MAO metabolize norepinephrine into vanillylmandelic acid (VMA).

N-methyltransferase, using a methyl group donated by SAM.

adrenal medulla makes epinephrine

COMT metabolizes epinephrine into metanephrine, which is converted to VMA by MAO

1) NE and epi
2) MOA
3) COMT breaksdown further to VMA

Heme is a component of hemoglobin, myoglobin, and cytochromes that is synthesized in most tissues of the body

(1) When porphyrinogen compounds in voided urine are oxidized and exposed to light, they become porphyrins, which have a red wine color and fluoresce under ultraviolet (UV) light.

1) Porphyrins in the peripheral circulation absorb ultraviolet light near the skin surface, becoming photosensitizing agents that damage skin and produce vesicles and bullae

1) Glycine and succinyl CoA are combined by the mitochondrial enzyme δ-aminolevulinic acid synthase (ALA synthase)

ALA synthase

1) requires PLP, derived from vitamin B6, as a cofactor
2) heme suppresses ALA synthase

1) alcohol
2) barbiturates

(1) δ-Aminolevulinic acid is converted to porphobilinogen by the cytosolic enzyme δ-aminolevulinic acid dehydratase (ALA dehydratase).

1) lead
2) leading to an increase in δ-aminolevulinic acid.

(1) Porphobilinogen is converted to hydroxymethylbilane by the cytosolic enzyme uroporphyrinogen I synthase

Uroporphyrinogen I synthase

(1) Hydroxymethylbilane is converted to uroporphyrinogen III by the cytosolic enzyme uroporphyrinogen III cosynthase
(2) Some hydroxymethylbilane is nonenzymatically converted to uroporphyrinogen I, which is further converted to coproporphyrinogen I.
(3) Uroporphyrinogen I and coproporphyrinogen I are spontaneously oxidized into uroporphyrin I and coproporphyrin I, respectively

congenital erythropoietic porphyria.

(1) Uroporphyrinogen III is converted to coproporphyrinogen III by the cytosolic enzyme uroporphyrinogen decarboxylase

porphyria cutanea tarda, the most common porphyria in the United States.

(1) Coproporphyrinogen III is converted to protoporphyrinogen IX
(2) protoporphyrinogen IX enters mitochondria and becomes protoporphyrin IX

ferrochetolase adds Fe2+ to it to make heme

1) lead
2) protoporhyrin accumulates

(1) Oxidases convert free heme to bilirubin in macrophages located in the spleen
(2) Unconjugated bilirubin (indirect bilirubin) combines with albumin in the blood and is taken up into hepatocytes by binding proteins.
(3) Unconjugated bilirubin is not filtered in urine, because it is lipid soluble and bound to albumin.

(1) In the hepatocytes, unconjugated bilirubin is conjugated by reacting with two molecules of glucuronic acid, a reaction that is catalyzed by uridine diphosphate glucuronyltransferase (UGT).
(2) Bilirubin diglucuronide, or conjugated (direct) bilirubin, is water soluble.
(3) Conjugated bilirubin does not have access to the blood unless there is inflammation in the liver (e.g., hepatitis) or obstruction to bile flow (e.g., gallstone in the common bile duct).
(4) Conjugated bilirubin is actively secreted into the bile ducts and stored in the gallbladder for eventual release into the duodenum.

1) Intestinal bacteria hydrolyze conjugated bilirubin and reduce free bilirubin to colorless urobilinogen.
2) Oxidation of urobilinogen yields urobilin, which gives feces its characteristic brown color

(1) Approximately 20% of urobilinogen is reabsorbed back into the blood (i.e., enterohepatic circulation) in the terminal ileum and is recycled to the liver and kidneys.
(2) In urine, urobilinogen is oxidized into urobilin, which gives urine its yellow color.
(3) The color of stool and urine is caused by urobilin.

1) autosomal dominant (AD) disorder
2) defect in ankyrin, the contractile protein attached to the inner surface of an RBC that helps maintain its characteristic shape.
3) predominantly unconjugated bilirubin

1) benign autosomal dominant disorder
2) defect in the uptake and conjugation of bilirubin
3) second only to hepatitis as the most common cause of jaundice in the United States
4) unconjugated bilirubin

1) partial (AD) or a total (AR) deficiency of UGT, the latter being incompatible with life.
2) unconjugated bilirubin

Mixed hyperbilirubinemia: between 20% and 50% conjugated bilirubin

1) AD
2) Uroporphyrinogen I synthase: catalyzes conversion of porphobilinogen to hydroxymethylbilane
3) Deficiency leads to increased levels of PBG and δ-ALA in urine

1) Recurrent attacks of neurologically induced abdominal pain (mimics a surgical abdomen)
2) Abdominal pain often leads to surgical exploration (bellyful of scars) without finding any cause
3) Urine exposed to light develops a red wine color due to porphobilin (i.e., window sill test)
4) peripheral neuropathy
5) psychiatric disorders
6) tachycardia

1) Porphobilinogen deaminase
2) hydroxymethylbilane synthase

1) Enzyme assay for RBCs is the confirming test when the patient is asymptomatic
2) Attacks precipitated by drugs that induce the liver cytochrome P450 system (e.g., alcohol, barbituates); drugs that induce ALA synthase (e.g., progesterone); and dietary restriction
3) Treatment: carbohydrate loading and infusion of heme, both of which inhibit ALA synthase activity

1) AR
2) Uroporphyrinogen III cosynthase: catalyzes conversion of hydroxymethylbilane to uroporphyrinogen III
3) Deficiency leads to increased levels of uroporphyrinogen I and its oxidation product uroporphyrin I

1) Hemolytic anemia and photosensitive skin lesions with vesicles and bullae
2) Uroporphyrin I produces a red wine color in urine and teeth and induces a photosensitivity reaction in skin
3) infant may scream in sunlight
4) splenomegaly
5) Treatment: protection of skin from light; bone marrow transplantation

1) autosomal dominant or acquired
2) Uroporphyrinogen decarboxylase: catalyzes conversion of uroporphyrinogen III to coproporphyrinogen III
2) Deficiency leads to accumulation of uroporphyrinogen III, which spontaneously converts into uroporphyrinogen I and coproporphyrinogen I and their respective oxidized porphyrins

1) Predominantly associated with photosensitive skin lesions consisting of vesicles and bullae and liver disease (e.g., cirrhosis)
2) Uroporphyrin I produces a red wine color in urine and predisposes to photosensitive skin lesions; PBG levels are normal

2) Exacerbating factors include iron 1) iron therapy, alcohol, estrogens, and hepatitis C (most common acquired cause of PCT)
2) Treatment: phlebotomy (reduce iron levels in the liver) and chloroquine

1) Inhibits ALA dehydratase and ferrochelatase:
a. ALA dehydratase catalyzes conversion of δ-ALA to PBG; inhibition leads to increased δ-ALA levels in urine
b. Ferrochelatase combines iron with protoporphyrin IX to form heme; Inhibition causes increased levels of RBC protoporphyrin IX and decreased heme

1) Iron accumulates in mitochondria, causing a microcytic anemia with ringed sideroblasts (mitochondria around the RBC nucleus filled with iron) in the bone marrow
2) Lead inhibits ribonuclease, causing persistence of ribosomes in peripheral blood RBCs (coarse basophilic stippling)

1) Causes include exposure to lead-based paint (e.g., pottery) and working in battery factories
2) Children develop encephalopathy with convulsions, microcytic anemia, colicky abdominal pain
3) Adults develop abdominal pain and diarrhea, peripheral neuropathies, and renal disease (e.g., aminoaciduria, renal tubular acidosis)
Screen for blood lead levels
4) Treatment: British antilewisite, calcium disodium edetate, and d-penicillamine

1) kernicterus
2) type II is only partial deletion
both have defective uridine diphosphate gluconyl transferase (UDP-GT)