Chemistry and Metabolism of Amino Acids - 2 | Biochemistry - NEET PG PDF Download

Synthesis of Melanin

• Location: Occurs in the melanosome of melanocytes in deeper epidermis layers.
• Regulation: Influenced by Melanocyte-Stimulating Hormone (MSH).
• Function: Melanin provides pigmentation to skin and hair.
• Key Enzyme: Tyrosinase
  • Role: Rate-limiting step in melanin synthesis.
  • Type: Monooxygenase.
  • Cofactor: Copper (Cu²⁺).
  • Function: Catalyzes two reactions converting tyrosine to DOPA and then to dopaquinone.

Synthesis of Catecholamines

• Catecholamines: Dopamine, Epinephrine, Norepinephrine.
• Structure: Contain a catechol nucleus.
• Synthesis Sites: Chromaffin cells of adrenal medulla and sympathetic ganglia.
  • Adrenal Medulla: Primarily produces epinephrine (80%).
  • Sympathetic Nerves: Primarily produces norepinephrine (80%).
• Note: Epinephrine is also known as adrenaline.
• Steps of Synthesis from Tyrosine to Epinephrine:
  1. Ring Hydroxylation: Tyrosine to DOPA by tyrosine hydroxylase.
  2. Decarboxylation: DOPA to dopamine by DOPA decarboxylase.
  3. Side Chain Hydroxylation: Dopamine to norepinephrine.
  4. N-Methylation: Norepinephrine to epinephrine.
• Key Enzyme: Tyrosine Hydroxylase
  • Role: Rate-limiting step.
  • Type: Monooxygenase.
  • Cofactor: Tetrahydrobiopterin.
  • Similarity: Similar to phenylalanine hydroxylase.
• Tyrosinase vs. Tyrosine Hydroxylase:
  • Tyrosinase: Expressed in melanocytes, uses Cu²⁺, produces DOPA for melanin.
  • Tyrosine Hydroxylase: Expressed in catecholamine synthesis sites, uses tetrahydrobiopterin, produces DOPA for catecholamines.
• DOPA Decarboxylase:
  • Location: Present in all tissues.
  • Coenzyme: Pyridoxal Phosphate (PLP).

Degradation of Catecholamines

Half-Life: 2–5 minutes.

Enzymes:

• Catechol O-Methyl Transferase (COMT): Initial catabolism of epinephrine and norepinephrine.
• Monoamine Oxidase (MAO): Further degradation.

End Products:

• Epinephrine/Norepinephrine: Vanillyl Mandelic Acid (VMA).
  • Urinary Excretion: 2–6 mg/24 hours.
• Dopamine: Homovanillic Acid (HVA).

Synthesis of Thyroid Hormones

Substrate: Thyroglobulin (large iodinated glycosylated protein with 115 tyrosine residues).

Process:

• Tyrosine residues iodinated to form Mono-IodoTyrosine (MIT) and Di-IodoTyrosine (DIT).
• Coupling reactions:
  • MIT + DIT → Tri-iodothyronine (T3).
  • DIT + DIT → Tetra-iodothyronine (T4, Thyroxine).

Clinical Correlations: Phenylalanine and Tyrosine Metabolism

Metabolic Disorders of Phenylalanine and Tyrosine Catabolism

Phenylketonuria (PKU):

• Type: Classic PKU (Type I).
• Prevalence: Most common amino acid metabolic disorder.
• Biochemical Defect: Phenylalanine hydroxylase deficiency.
  • Phenylalanine cannot be converted to tyrosine.
  • Leads to elevated phenylalanine levels in blood.
  • Alternate pathways produce phenylketones (phenylpyruvate, phenylacetate), excreted in urine.
• Clinical Presentation:
  • Normal at birth.
  • Untreated: Progressive intellectual disability, vomiting (may mimic pyloric stenosis), hyperactivity, autistic behaviors (hand movements, rocking, athetosis).
  • Lighter complexion due to reduced melanin synthesis.
  • Musty/mousey odor from phenylacetic acid.
  • CNS damage due to high phenylalanine levels inhibiting transport of other large neutral amino acids (tyrosine, tryptophan) across the blood-brain barrier.
• Lab Diagnosis:
  • Guthrie’s Test: Bacterial inhibition assay, rapid blood screening using Bacillus subtilis (growth proportional to phenylalanine).
  • Ferric Chloride Test: Detects phenylketones in urine (outdated in developed countries).
  • Tandem Mass Spectrometry: Method of choice, identifies all hyperphenylalaninemia forms.
  • Other Methods: Molecular biology (phenylalanine hydroxylase probes), quantitative blood phenylalanine (>20 mg/dl), enzyme assay in dry blood spots.
• Treatment:
  • Low-phenylalanine diet.
  • Large Neutral Amino Acids (LNAAs) supplementation to compete with phenylalanine for transport across blood-brain barrier.
  • Sapropterin dihydrochloride (Kuvan): Synthetic tetrahydrobiopterin (BH4) for patients with residual phenylalanine hydroxylase activity.
  • Recombinant phenylalanine ammonia lyase trials.
• Nonclassical PKU:
  • Biochemical Defect: Tetrahydrobiopterin deficiency.
    • Type II & III: Dihydrobiopterin reductase defect.
    • Type IV & V: Defects in tetrahydrobiopterin synthesis enzymes (6-pyruvoyltetrahydropterin synthase, GTP cyclohydrolase).
  • Lab Diagnosis:
    • Measurement of neopterin and biopterin in urine.
    • Tetrahydrobiopterin (BH4) loading test normalizes plasma phenylalanine.
    • Enzyme assay in dry blood spots.
    • Genetic mutation analysis.
• Alkaptonuria:
  • Inheritance: Autosomal recessive, part of Garrod’s Tetrad (Alkaptonuria, Albinism, Pentosuria, Cystinuria).
  • Biochemical Defect: Homogentisate oxidase deficiency.
    • Accumulation of homogentisic acid, polymerizes to alkaptone bodies.
• Clinical Presentation:
  • Normal until 3rd/4th decade.
  • Children: Urine darkens on standing.
  • Adults: Ochronosis (alkaptone deposition in intervertebral disks, cartilage), arthritis.
  • No mental retardation.
• Lab Diagnosis:
  • Alkalinization darkens urine.
  • Positive Benedict’s, ferric chloride, silver nitrate tests (homogentisic acid is a reducing agent).
• Treatment:
  • Nitisinone (NTBC): Inhibits para-hydroxyphenylpyruvate hydroxylase to reduce homogentisic acid.
  • Symptomatic treatment.

Tyrosinemia:

• Type I (Hepatorenal Tyrosinemia):
  • Biochemical Defect: Fumarylacetoacetate hydrolase deficiency.
  • Affected Organs: Liver, kidney, peripheral nerves.
  • Cause of Damage: Accumulation of fumarylacetoacetate and succinylacetone.
  • Odor: Cabbage-like due to succinylacetone.
  • Diagnosis: Elevated succinylacetone in urine/blood (plasma tyrosine less diagnostic).
  • Treatment: Low phenylalanine/tyrosine diet, Nitisinone.
• Type II (Oculocutaneous Tyrosinemia):
  • Biochemical Defect: Tyrosine transaminase deficiency.
  • Clinical Features: Palmar/plantar hyperkeratosis, herpetiform corneal ulcers, intellectual disability.
• Type III (Neonatal Tyrosinemia):
  • Biochemical Defect: Para-hydroxyphenylpyruvate hydroxylase (4-HPPD) deficiency.

Hawkinsinuria:

• Inheritance: Autosomal dominant.
• Biochemical Defect: Missense mutations in para-hydroxyphenylpyruvate hydroxylase.
  • Mutant enzyme forms hawkinsin (reacts with cysteine) instead of homogentisic acid.
  • Secondary glutathione deficiency.
  • Odor: Swimming pool-like.

Segawa Syndrome:

• Biochemical Defect: GTP cyclohydrolase deficiency (tetrahydrobiopterin deficiency).
• Features: No hyperphenylalaninemia, autosomal dominant, dystonia with diurnal variation, females more affected.

Albinism:

• Biochemical Defect: Tyrosinase deficiency (melanin synthesis).
• Types:
  • Oculocutaneous Albinism (OCA):
    • OCA-1: Tyrosinase deficient.
    • OCA-2: Tyrosinase positive (most common).
    • OCA-3: Rufous/red OCA.
  • Syndromes: Prader-Willi, Angelman, Hermansky-Pudlak, Chédiak-Higashi.
  • Ocular Albinism: Nettleship-Falls type.
  • Localized Albinism: Piebaldism, Waardenburg syndrome.

Pheochromocytoma:

• Description: Catecholamine-producing tumors (adrenal/extra-adrenal).
• Clinical Triad: Palpitations, headaches, profuse sweating, associated with hypertension.
• Biochemical Testing:
  • Elevated plasma/urinary catecholamines, metanephrines, VMA.
  • Tests:
    • Urinary: VMA, catecholamines, fractionated/total metanephrines.
    • Plasma: Catecholamines, free metanephrines.
• Associated Syndromes: Neurofibromatosis type 1, Multiple Endocrine Neoplasia (MEN) 2A/2B.

Tryptophan Metabolism

Characteristics:

• Aromatic, essential amino acid.
• Contains indole group.
• Glucogenic and ketogenic.

Catabolic Pathway: Kynurenine-Anthranilate Pathway.

• Key Enzyme: Tryptophan Pyrrolase (Tryptophan Oxygenase).
  • Type: Dioxygenase, heme-containing.
• Kynureninase:
  • Coenzyme: PLP.
  • Deficiency: Leads to reduced NAD+ synthesis, niacin deficiency, pellagra-like symptoms, xanthurenate excretion in urine.

Specialized Products:
Niacin (Nicotinic Acid):

• 3% of tryptophan enters this pathway.
• 60 mg tryptophan → 1 mg niacin.
• Rate-Limiting Enzyme: Quinolinate Phosphoribosyl Transferase.

Serotonin (5-Hydroxytryptamine):

• Synthesis Sites: Argentaffin cells (intestine), mast cells, platelets, brain.
• Functions: Neurotransmitter, mood elevation, GI motility, temperature regulation, vasoconstriction.
• Key Enzyme: Tryptophan Hydroxylase.
  • Role: Rate-limiting step, converts tryptophan to 5-hydroxytryptophan.
  • Cofactor: Tetrahydrobiopterin.
• Amino Acid Decarboxylase: Converts 5-hydroxytryptophan to serotonin (PLP coenzyme).
• Catabolism: By monoamine oxidase, produces 5-Hydroxyindoleacetic Acid (5-HIAA).
  • Urinary Excretion: <5 mg/day.

Melatonin:

• Synthesis Site: Pineal gland.
• Process: N-acetylation of serotonin followed by N-methylation (methyl donor: S-Adenosyl Methionine).
• Functions: Diurnal variation, biological rhythm, sleep-wake cycle.

Metabolic Disorders:

Carcinoid Syndrome:

• Description: Gastrointestinal neuroendocrine tumor of argentaffin cells, overproduces serotonin.
• Symptoms: Intermittent diarrhea (32–84%), flushing (63–75%), sweating, fluctuating hypertension, pellagra-like symptoms.
• Diagnosis: Elevated serum serotonin, urinary 5-HIAA, neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin).
• Typical Carcinoid:
  • Midgut tumor, increased serotonin synthesis, elevated blood/platelet serotonin, urinary 5-HIAA.
• Atypical Carcinoid:
  • Foregut tumor, aromatic amino acid decarboxylase deficiency.
  • 5-Hydroxytryptophan secreted, normal plasma serotonin, increased urinary 5-HTP/5-HT, slightly elevated 5-HIAA.

Hartnup Disorder:

• Inheritance: Autosomal recessive.
• Biochemical Defect: Defective absorption of tryptophan and neutral amino acids (BOAT1 transporter, SLC6A19 gene).
• Clinical Features: Asymptomatic, cutaneous photosensitivity, intermittent ataxia, pellagra-like symptoms (due to niacin deficiency).
• Diagnosis: Positive Obermeyer test (indole compounds in urine).
• Treatment: Lipid-soluble amino acid esters, nicotinic acid/nicotinamide (50–300 mg/24 hr), high-protein diet.

Blue Diaper Syndrome:

• Biochemical Defect: Tryptophan malabsorption in intestine (not kidney).
• Feature: Blue diaper staining due to bacterial breakdown of unabsorbed tryptophan to indican and indigoblue.

Simple Amino Acids

Glycine

Characteristics: Simplest, nonessential, glucogenic, optically inactive.

Biosynthesis:

• From glyoxylate, glutamate, alanine by glycine aminotransferase.
• From serine by serine hydroxymethyltransferase (reversible, requires PLP and folic acid).
• From threonine by threonine aldolase.
• In invertebrates: Glycine synthase system.
  

Catabolism: Glycine Cleavage System (liver mitochondria).

• Components:
  • Glycine dehydrogenase.
  • Aminomethyltransferase.
  • Dihydrolipoamide dehydrogenase.
  • H protein (dihydrolipoyl moiety).
• Reaction: Glycine + THFA + NAD⁺ → CO₂ + NH₃ + N5,N10-Methenyl THFA + NADH + H⁺.
• Specialized Products:
  • Creatine, creatine phosphate, creatinine.
  • Heme.
  • Purine nucleotides (C4, C5, N7 of purine ring).
  • Glutathione.
• Functions:
  • Conjugation: Bile acids (glycocholic acid), benzoic acid (hippuric acid).
  • Neurotransmitter: Excitatory and inhibitory.
  • Collagen: Every third amino acid is glycine.
• Creatinine Synthesis:
  • Amino Acids: Glycine, arginine, methionine.
  • Steps:
    1. Kidney: Glycine + arginine → guanidinoacetic acid (glycine arginine amidotransferase).
    2. Liver: Guanidinoacetic acid → creatine (guanidinoacetate methyltransferase, SAM as methyl donor).
    3. Muscle: Creatine → creatine phosphate (creatine kinase).
    4. Spontaneous: Creatine phosphate → creatinine.

Glutathione:

Composition: Gamma-glutamyl-cysteinyl-glycine (tripeptide, pseudopeptide).

• Functions:
  • Meister’s cycle: Amino acid transport (intestine, kidney, brain, 3 ATP/mol).
  • Free radical scavenging (RBC membrane integrity).
  • Reduction of methemoglobin (keeps heme iron ferrous).
  • Conjugation in phase II xenobiotic reactions (glutathione S-transferase).
  • Coenzyme for some reactions.
• Derivatives:
  • Sarcosine: N-methyl glycine.
  • Betaine: Trimethyl glycine.
• Metabolic Disorders:
• Primary Hyperoxaluria Type I:
  • Biochemical Defect: Alanine-glyoxylate aminotransferase deficiency (liver peroxisomes, pyridoxine cofactor).
  • Feature: Protein targeting defect.
• Primary Hyperoxaluria Type II:
  • Biochemical Defect: D-glycerate dehydrogenase/glyoxylate reductase deficiency.
• Secondary Hyperoxaluria:
  • Pyridoxine deficiency.
  • Ethylene glycol ingestion.
  • High vitamin C doses.
  • Methoxyflurane anesthesia.
  • Inflammatory bowel disease/ bowel resection.
• Nonketotic Hyperglycinemia:
  • Biochemical Defect: Glycine cleavage system deficiency.

Alanine

• Characteristics: Simple, nonessential, principal glucogenic amino acid.
• Functions:
  • Transports amino groups from skeletal muscle.
  • Participates in glucose-alanine cycle (Cahill cycle).
• Biosynthesis: From pyruvate by transamination.

Serine

• Characteristics: Hydroxyl group-containing, glucogenic, nonessential, polar.
• Biosynthesis:
  • From glycine by serine hydroxymethyltransferase (PLP coenzyme).
  • From 3-phosphoglycerate (glycolytic intermediate).
• Vitamins: Folic acid, pyridoxine for serine-to-glycine conversion.
• Metabolic Functions:
  • Primary donor of one-carbon groups.
  • Precursor for cysteine (serine + homocysteine → cysteine + homoserine).
  • Phospholipid synthesis (phosphatidylserine).
  • Drug analogs: Cycloserine (antituberculous), azaserine (anticancer).
  • Synthesis of ethanolamine, choline, betaine.
  • Precursor of selenocysteine.
  • O-glycosylation at serine/threonine residues.
  • Phosphorylation sites (serine/threonine).
  • Sphingosine synthesis (serine + palmitoyl CoA → ceramide → sphingolipids).

Sulfur-Containing Amino Acids

Methionine

Characteristics: Essential, glucogenic.

Metabolism:

• Step 1: Conversion to S-adenosyl methionine (SAM) by methionine adenosyl transferase (MAT).
  • Isoenzymes: MAT-I, MAT-III (liver), MAT-II (extrahepatic).
  • Function: SAM is the principal methyl donor (methyl group labile due to adenosyl group).
• Step 2: SAM to homocysteine.

Fates of Homocysteine:

1. Resynthesis of Methionine: Methyl group transfer from N5-methyl THFA (vitamin B12, folate).
2. Cysteine Synthesis (Transsulfuration):
   • Homocysteine + serine → cystathionine (cystathionine beta synthase, PLP).
   • Cystathionine → cysteine + homoserine (cystathionase, PLP).
   • Homoserine → propionyl CoA → succinyl CoA.

Functions of SAM:

• Transmethylation (e.g., guanidinoacetate → creatine, norepinephrine → epinephrine).
• DNA methylation.
• Polyamine synthesis:
  • Ornithine → putrescine (ornithine decarboxylase, rate-limiting).
  • SAM (decarboxylated) donates carbons/amino group to form spermidine, spermine.
  • Polyamine Functions: DNA/RNA stabilization, cell proliferation, growth, membrane stabilization, carcinogenesis.
• Vitamins:
  • Vitamin B12, folic acid: Methionine synthase.
  • Vitamin B6: Cystathionine beta synthase, cystathionase.
• Folate Trap:
  • Vitamin B12 deficiency blocks N5-methyl THFA to THFA conversion.
  • Folate trapped as N5-methyl THFA, causing THFA starvation and impaired one-carbon metabolism.
  • Homocysteine accumulates (risk for acute coronary syndrome).
    

Cysteine

• Characteristics: Nonessential, glucogenic.
• Specialized Products:
  • Cystine (condensation of two cysteines).
  • Taurine.
  • Glutathione.
  • Betamercaptoethanolamine (from decarboxylation).
  • Coenzyme A.
• Role in Aging:
  • Cysteine and taurine decrease aging (aging as cysteine deficiency syndrome).
  • Homocysteine accelerates aging.

Metabolic Disorders

Classic Homocystinuria:

Biochemical Defect: Cystathionine beta synthase deficiency.

• Homocysteine not converted to cysteine (cysteine deficiency).
• Excess homocysteine → methionine (hypermethioninemia).

Clinical Features:

• Normal at birth, nonspecific infancy symptoms (failure to thrive, developmental delay).
• After age 3: Ectopia lentis (severe myopia, iridodonesis), intellectual disability, Marfan-like skeletal abnormalities, fair complexion, malar flush, thromboembolism.

Diagnosis:

• Elevated methionine, homocystine; low cystine in plasma.
• Cyanide nitroprusside test (urine, homocystine unstable).
• Enzyme analysis (liver, fibroblasts), DNA mutation analysis.

Treatment:

• High-dose vitamin B6 (200–1000 mg/24 hr).
• Folic acid (1–5 mg/24 hr) for non-responders.
• Methionine restriction, cysteine supplementation.
• Betaine (remethylates homocysteine to methionine).
• Vitamin C (1 g/day) for endothelial function.

Nonclassic Homocystinuria:

Causes:

1. Methylcobalamin Formation Defect:
   • Methionine synthase cofactor deficiency.
   • Homocysteine accumulation, hypomethioninemia, megaloblastic anemia.
   • Treatment: Hydroxycobalamin (1–2 mg/24 hr).
2. Methylenetetrahydrofolate Reductase (MTHFR) Deficiency:
   • Blocks N5,N10-methylene THFA to N5-methyl THFA.
   • Hypomethioninemia, homocystinemia, no megaloblastic anemia.
   • Treatment: Folic acid, vitamin B6, B12, methionine, betaine.

Cystathioninuria:

• Biochemical Defect: Cystathionase deficiency.
• Features: Mental retardation, anemia, thrombocytopenia.
• Diagnosis: Negative cyanide nitroprusside test.

Cystinuria:

• Description: Part of Garrod’s Tetrad.
• Biochemical Defect: Defective dibasic amino acid transporter (cystine, ornithine, lysine, arginine; COLA).
• Features: Cystine stones in urine.
• Diagnosis: Positive cyanide nitroprusside test.
• Treatment: Hydration, urine alkalinization.

Oasthouse Syndrome:

• Biochemical Defect: Malabsorption of methionine and neutral amino acids.

Hypermethioninemia:

• Biochemical Defect: Hepatic methionine adenosyl transferase (MAT I, III) deficiency.
• Feature: Boiled cabbage odor.

Cystinosis:

• Description: Lysosomal storage disorder.
• Biochemical Defect: CTNS gene mutation (cystinosin, H⁺-driven cystine transporter).
• Features: Cystine crystal accumulation in kidney, liver, eye, brain.
• Diagnosis: Corneal cystine crystals, elevated leukocyte cystine.
• Treatment: Cysteamine (converts cystine to cysteine), kidney transplantation.

Branched Chain Amino Acids

• Amino Acids:
  • Valine: Glucogenic.
  • Leucine: Ketogenic.
  • Isoleucine: Glucogenic and ketogenic.
• Characteristics: All essential.
• Common Metabolic Steps:
  1. Transamination: Branched chain amino acid transaminase (PLP).
  2. Oxidative Decarboxylation: Branched chain ketoacid dehydrogenase (thiamine pyrophosphate, FAD, NAD⁺, lipoamide, CoA).
  3. Dehydrogenation: Acyl CoA dehydrogenase (FAD).
• Metabolic Fates:
  • Leucine: Ketogenic pathway.
  • Valine: Glucogenic pathway.
  • Isoleucine: Both pathways.
• Metabolic Disorders:
• Maple Syrup Urine Disease (MSUD):
• Biochemical Defect: Branched chain ketoacid dehydrogenase deficiency (defective decarboxylation).
• Components:
  • Type IA: E1α (decarboxylase, TPP).
  • Type IB: E1β (decarboxylase).
  • Type II: E2 (dihydrolipoyl transacylase, lipoamide).
  • Type III: E3 (dihydrolipoamide dehydrogenase, FAD).
• Clinical Features:
  • Normal at birth, poor feeding, vomiting in first week.
  • Lethargy, coma, convulsions, metabolic acidosis, hypertonicity, opisthotonos, alternating flaccidity.
  • Maple syrup odor in urine, sweat, cerumen.
  • Mental retardation.
• Diagnosis:
  • Elevated plasma leucine, isoleucine, valine, alloisoleucine.
  • Urinary leucine, isoleucine, valine, ketoacids.
  • Dinitrophenylhydrazine (DNPH) test, Rothera’s test.
  • Enzyme analysis (leukocytes, fibroblasts), tandem mass spectrometry.
• Treatment: Restrict branched chain amino acids, high-dose thiamine.
  • Isovaleric Aciduria:
    • Biochemical Defect: Isovaleryl CoA dehydrogenase deficiency (leucine metabolism).
    • Feature: Sweaty feet odor.
• Intermittent Branched Chain Ketonuria:
  • Partial activity of branched chain α-ketoacid decarboxylase.

Basic Amino Acids

Lysine

• Characteristics: Essential, predominantly ketogenic, represented by letter K.
• Functions:
  • Hydroxylysine: Collagen cross-links, desmosine in elastin.
  • Forms Schiff’s bases.
  • Precursor of carnitine (with methionine).
  • Decarboxylation forms cadaverine.
  • Histone proteins are lysine-rich.
• Catabolism: Saccharopine intermediate.

Arginine

• Characteristics: Glucogenic, semiessential.
• Metabolic Pathway: L-glutamate semialdehyde → α-ketoglutarate.
• Functions:
  • Nitric oxide synthesis.
  • Agmatine synthesis (decarboxylation, neurotransmitter, antihypertensive).
  • Urea cycle (arginine → ornithine + urea).
  • Creatine synthesis.
• Nitric Oxide (NO):
  • Properties: Uncharged, free radical, short half-life (0.1 s), gaseous, cGMP second messenger.
  • Functions:
    • Vasodilator.
    • Penile erection.
    • Neurotransmitter.
    • Inhibits platelet adhesion/activation.
    • Low NO linked to pylorospasm in hypertrophic pyloric stenosis.
• Therapeutic Uses:
  • Inhaled NO for pulmonary hypertension.
  • Sildenafil (cGMP phosphodiesterase inhibitor) for impotence.
  • Glyceryl nitrite for angina pectoris.
• Synthesis: By nitric oxide synthase (NOS, cytosolic monooxygenase).
  • Cofactors: NADPH, FAD, FMN, heme, tetrahydrobiopterin.
  • Isoforms:
    • nNOS: Neuronal, Ca²⁺-activated, deficiency causes pyloric stenosis, aggressive sexual behavior.
    • iNOS: Macrophage, Ca²⁺-independent, deficiency increases infection susceptibility.
    • eNOS: Endothelial, Ca²⁺-activated, deficiency causes elevated blood pressure.
• Mechanism: Ca²⁺ activates NOS → NO release → activates guanylyl cyclase → cGMP → smooth muscle relaxation.

Histidine

• Characteristics: Semiessential, contains imidazole ring, maximum buffering at physiological pH.
• Metabolism:
  • Derivatives: Urocanate, FIGLU (formimino glutamic acid).
  • Folic Acid Deficiency: FIGLU excretion in urine (histidine load test).
• Biologically Important Compounds:
• Histamine: From decarboxylation (PLP coenzyme).
  • Functions:
    • H1 Receptor: Smooth muscle contraction, vascular permeability.
    • H2 Receptor: Gastric HCl secretion.
    • H3 Receptor: Histamine synthesis/release in brain.
  • Carnosine (β-alanyl histidine), anserine (methyl carnosine), homocarnosine, ergothionine.
• Metabolic Disorder: Histidinemia (histidase deficiency).

Acidic Amino Acids

Glutamic Acid (Glutamate)

• Characteristics: Nonessential, glucogenic, central role in amino acid metabolism.
• Biosynthesis: Reductive amidation of α-ketoglutarate by glutamate dehydrogenase.
• Functions:
  • Concentrates amino groups from all amino acids via transamination.
  • Synthesis of N-acetyl glutamate (regulates urea cycle).
  • Glutathione synthesis.
  • Gamma-amino butyric acid (GABA) synthesis (decarboxylation, PLP coenzyme).

Glutamine

• Biosynthesis: From glutamic acid by glutamine synthetase.
• Functions:
  • Traps inorganic ammonium ions (first-line ammonia trapping).
  • Transports amino groups from brain/other tissues.
  • Contributes N3, N9 (purine), N3 (pyrimidine).
  • Source of ammonia for guanine, cytosine.
  • Conjugating agent.
  • Ammonia excretion in kidney (acid-base balance).

Aspartic Acid (Aspartate)

• Characteristics: Nonessential, glucogenic.
• Biosynthesis: Transamination of oxaloacetate.
• Functions:
  • Contributes amino group to urea synthesis.
  • Purine and pyrimidine synthesis.
• Metabolic Disorder: Canavan Disease.
  • Inheritance: Autosomal recessive, prevalent in Ashkenazi Jews.
  • Biochemical Defect: Aspartoacylase deficiency.
    • Accumulation of N-acetylaspartic acid (possible acetate reservoir for myelin).
  • Features: Leukodystrophy, excessive N-acetylaspartic acid excretion.
  • Diagnosis: Aspartoacylase deficiency in fibroblasts, urinary N-acetylaspartic acid.

Asparagine

• Biosynthesis: From aspartate by asparagine synthetase (uses glutamine, not ammonium ions).
• Catabolism:
  • Glutamate, glutamine → α-ketoglutarate.
  • Aspartate, asparagine → oxaloacetate.

Amino Acids and TCA Cycle

• To α-Ketoglutarate: Arginine, histidine, glutamine, proline (via glutamate).
• To Succinyl CoA: Valine, isoleucine, methionine, threonine.
• To Fumarate: Tyrosine, phenylalanine, aspartate.
• To Oxaloacetate: Asparagine (via aspartate).

Quick Review Points

• UV Light Absorption: Tryptophan, phenylalanine, tyrosine.
• No Asymmetric Carbon: Glycine.
• β-Alanine Source: Uracil, cytosine.
• Isoelectric pH: Amino acid has no net charge.
• Oxidative Deamination: Glutamate.
• Transamination Coenzyme: PLP.
• Ammonia Transport:
  • Glutamine: Brain, most organs.
  • Alanine: Skeletal muscle.
• Urea Nitrogen: Ammonia, aspartate.
• Urea Cycle Rate-Limiting Step: Carbamoyl phosphate synthetase I.
• Common Urea Cycle Disorder: Hyperammonemia Type II (ornithine transcarbamoylase defect).
• Polyamine Precursors: Ornithine, methionine, lysine.
• Cahill Cycle: Alanine.
• Gluconeogenic in Starvation: Alanine.
• ​​​​Carnitine Precursors: Lysine, methionine.
• Selenocysteine Precursor: Serine.
• Glutamic Acid Products: GABA, α-ketoglutarate.
• Folate Trap: THFA as methyl derivative.

Metabolic Disorders and Biochemical Defects

Specialized Products from Amino Acids

Peculiar Odors in Amino Acidurias