Topic Overview

⭐ PHENYLALANINE

Overview

• Essential aromatic amino acid

• Converted to tyrosine, which then forms melanin, thyroid hormones, and catecholamines.

Major Reaction

Phenylalanine → Tyrosine

Enzyme: Phenylalanine hydroxylase
Cofactor: Tetrahydrobiopterin (BH₄)
Byproduct: BH₂ (regenerated by dihydropteridine reductase)

Importance

• First step in enzymatic pathway to dopamine, adrenaline, noradrenaline, thyroid hormones, melanin

• Provides precursor for fumarate (glucogenic) and acetoacetate (ketogenic)

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⭐ TYROSINE

Properties

• Non-essential, but becomes conditionally essential in PKU

• Both glucogenic & ketogenic

Functions

• Precursor of:

  • Melanin

  • Catecholamines

  • Thyroid hormones (T3, T4)

  • Fumarate + Acetoacetate

  • Dopa and dopamine

  • Norepinephrine & Epinephrine

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⭐ MELANIN SYNTHESIS

Pathway

Tyrosine → DOPA → Dopaquinone → Melanin

Key Enzyme:

Tyrosinase (copper-dependent)

Types of Melanin

• Eumelanin: Brown-black

• Pheomelanin: Yellow-red

Clinical Notes

1. Albinism:

   • Defect in tyrosinase → no melanin

   • Pigment absent in skin, eyes, hair

2. Vitiligo:

   • Autoimmune destruction of melanocytes (melanin absent in patches)

3. Melasma / post-inflammatory pigmentation:

   • Excess melanin deposition

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⭐ CATECHOLAMINE SYNTHESIS

This is a crucial exam topic.

⭐ Full Pathway

Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine

Step 1: Tyrosine → DOPA

Enzyme: Tyrosine hydroxylase
Cofactor: BH₄
Rate-limiting step

Step 2: DOPA → Dopamine

Enzyme: DOPA decarboxylase
Cofactor: PLP (Vitamin B6)

Step 3: Dopamine → Norepinephrine

Enzyme: Dopamine β-hydroxylase
Cofactor: Vitamin C + Copper
Location: Inside vesicles

Step 4: Norepinephrine → Epinephrine

Enzyme: Phenylethanolamine N-methyltransferase (PNMT)
Methyl donor: SAM
Stimulated by: Cortisol

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⭐ CATECHOLAMINE DEGRADATION

Major enzymes

• MAO: Monoamine oxidase

• COMT: Catechol-O-methyl transferase

End products

• Vanillylmandelic acid (VMA): NE/Epinephrine breakdown

• Homovanillic acid (HVA): Dopamine breakdown

Clinical Uses

• High VMA → Pheochromocytoma

• High HVA → Neuroblastoma

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⭐ IMPORTANT DISORDERS (from Tyrosine & Catecholamine Pathways)

1. Phenylketonuria (PKU)

Caused by:

• Phenylalanine hydroxylase deficiency OR

• BH₄ deficiency

Features

• High phenylalanine

• Intellectual disability

• Seizures

• Musty/mousy odor

• Hypopigmentation (↓ tyrosine → ↓ melanin)

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2. Alkaptonuria

Defect: Homogentisate oxidase
→ Homogentisic acid accumulation

Signs

• Black urine on standing

• Ochronosis (bluish-black tissues)

• Early osteoarthritis

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3. Tyrosinemia Type I

Defect: Fumarylacetoacetate hydrolase

Features

• Liver failure

• Renal tubular dysfunction

• “Cabbage-like” odor

• Can lead to hepatocellular carcinoma

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⭐ Ultra-Short Revision

• Phenylalanine → tyrosine via BH₄-dependent hydroxylase.

• Melanin requires tyrosinase (Cu-dependent).

• Catecholamines: Tyrosine → DOPA → Dopamine → NE → E.

• PNMT converts NE → E (needs SAM & cortisol).

• PKU → high phenylalanine, low tyrosine, musty odor.

• Alkaptonuria → black urine, homogentisate oxidase defect.

• Tyrosinemia I → liver failure, cabbage odor.

 

⭐ PHENYLKETONURIA (PKU)

⭐ Cause

Defect in phenylalanine hydroxylase
OR
Defect in BH₄ (tetrahydrobiopterin) regeneration.

Phenylalanine → cannot convert to tyrosine → accumulates.

⭐ Biochemical Results

• ↑ Phenylalanine

• ↓ Tyrosine (becomes essential)

• ↑ Phenylpyruvate, phenylacetate, phenyllactate (ketones)

⭐ Clinical Features

• Severe intellectual disability (if untreated)

• Seizures

• Musty/mousy body odor

• Light hair & skin (↓ melanin)

• Eczema

• Developmental delay

• Microcephaly

⭐ Investigations

• Newborn screening: Guthrie test / tandem mass spectrometry

• Elevated phenylalanine in blood

⭐ Treatment

• Low phenylalanine diet (life-long)

• Tyrosine supplementation

• Avoid aspartame

• BH₄ supplementation (sapropterin) in BH₄-responsive cases

⭐ Key Points

• Tyrosine becomes essential.

• Mental retardation is preventable with newborn screening.

• Musty odor due to phenylacetate.

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⭐ ALKAPTONURIA

⭐ Cause

Deficiency of homogentisate oxidase, an enzyme in the tyrosine degradation pathway.

Tyrosine → homogentisate → ❌ cannot convert further.

⭐ Accumulated Metabolite

Homogentisic acid

⭐ Clinical Features

• Black urine on standing (air oxidation)

• Ochronosis

  • Bluish-black pigmentation of sclera, ear cartilage, nose

• Early-onset osteoarthritis (due to ochronotic pigment deposition in joints)

• Darkening of sweat or diapers

⭐ Diagnosis

• Elevated homogentisic acid in urine

• Characteristic black color on exposure to air/alkali

⭐ Treatment

• Mostly supportive

• High dose Vitamin C sometimes offered (questionable value)

• Low phenylalanine/tyrosine diet (milder benefit)

• Nitisinone (NTBC) used experimentally to reduce homogentisate production

⭐ Key Points

• Autosomal recessive

• Pigment deposition = hallmark

• Urine darkens only after standing, not fresh.

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⭐ ALBINISM

⭐ Definition

A group of disorders with absent or reduced melanin due to defects in melanin synthesis.

⭐ Most Common Type

Oculocutaneous albinism Type I

⭐ Cause

Deficiency of tyrosinase (Cu-dependent)
→ Tyrosine ❌ cannot convert to DOPA
→ No melanin

⭐ Clinical Features

• Very light skin, white hair

• Photophobia

• Nystagmus

• Decreased visual acuity

• Increased risk of sunburn, skin cancers

• Normal number of melanocytes, but lack melanin production

⭐ Diagnosis

• Clinical appearance

• Ophthalmic signs

• Molecular testing (if required)

⭐ Treatment

• UV protection (sunscreen, clothing)

• Ophthalmologic follow-up

• No specific cure

⭐ Key Points

• Melanocyte number = normal

• Enzyme defect → impaired melanin synthesis

• Tyrosinase is key

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⭐ Ultra-Short Revision

• PKU:

  • Phenylalanine hydroxylase or BH₄ defect

  • Musty odor, ↓ tyrosine, intellectual disability

  • Treat with low Phe diet + tyrosine

• Alkaptonuria:

  • Homogentisate oxidase defect

  • Black urine, ochronosis, early arthritis

• Albinism:

  • Tyrosinase defect

  • Normal melanocytes, ↓ melanin

 

 

⭐ TRYPTOPHAN

⭐ Overview

• Aromatic, essential amino acid

• Both glucogenic (alanine) and ketogenic (acetyl-CoA)

• Precursor of multiple biologically important molecules.

⭐ Major Products of Tryptophan

• Niacin (NAD⁺/NADP⁺)

• Serotonin (5-HT)

• Melatonin

• Kynurenine → NAD pathway

• Indole → Indican (excretory product)

• Formylkynurenine → formate (one-carbon pool)

⭐ Key Requirements

• Niacin synthesis from tryptophan requires:

  • Vitamin B6 (PLP)

  • Riboflavin (FAD)

  • Iron

• Hartnup disease reduces tryptophan absorption → pellagra-like symptoms.

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⭐ NICOTINIC ACID (NIACIN) PATHWAY

⭐ Pathway (Condensed)

Tryptophan → Kynurenine → 3-Hydroxykynurenine → 3-Hydroxyanthranilate → Quinolinate → NAD⁺ / NADP⁺

⭐ Key Points

• 60 mg tryptophan = 1 mg niacin (approx.)

• Requires Vitamin B6 (PLP)

• Deficiency → pellagra (“3 D’s”: dermatitis, diarrhea, dementia)

⭐ Conditions with Low Niacin Synthesis

• Hartnup disease (defective neutral amino acid transport → ↓ tryptophan)

• Carcinoid syndrome (majority of tryptophan shunted to serotonin pathway)

• Isoniazid therapy (B6 deficiency)

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⭐ SEROTONIN (5-Hydroxytryptamine, 5-HT)

⭐ Synthesis

Tryptophan → 5-Hydroxytryptophan → Serotonin (5-HT)

Enzymes

1. Tryptophan hydroxylase

   • Requires BH₄

2. Aromatic amino acid decarboxylase

   • Requires PLP (Vitamin B6)

⭐ Location

• Enterochromaffin cells of intestine (~90%)

• CNS neurons

• Platelets (uptake only)

⭐ Functions

• Mood regulation

• Sleep and appetite

• Gut motility

• Vasoconstriction

• Precursor for melatonin

⭐ Disorders

Carcinoid Syndrome

• Excess serotonin production by carcinoid tumor

• Features:

  • Diarrhea

  • Flushing

  • Wheezing

  • Right-sided heart lesions

• Investigation: High urinary 5-HIAA

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⭐ MELATONIN

⭐ Source

• Pineal gland

⭐ Synthesis

Serotonin → Melatonin

Enzymes

• N-acetyltransferase

• Hydroxy-indole-O-methyltransferase (uses SAM)

⭐ Functions

• Regulates sleep–wake (circadian) rhythm

• Antioxidant

• Modulates reproductive cycles

• Lower at daytime; highest at night

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⭐ INDICAN (Indoxyl sulfate)

⭐ Formation

• From bacterial degradation of tryptophan in the intestine:

  • Tryptophan → Indole → absorbed → liver → Indoxyl sulfate (Indican)

  • Excreted in urine.

⭐ Clinical Notes

Increased Indican

• Hartnup disease (poor absorption → more tryptophan reaches colon)

• Intestinal malabsorption

• Bacterial overgrowth

Diagnostic Significance

• Excess indican → blue diaper (reaction with air/oxidation)

• Seen in tryptophan malabsorption disorders

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⭐ Ultra-Short Revision Capsule

• Tryptophan → serotonin → melatonin

• Tryptophan → niacin (needs B6, Fe, FAD)

• Carcinoid → serotonin ↑, 5-HIAA ↑, niacin ↓

• Indican ↑ in tryptophan malabsorption

• Melatonin regulates circadian rhythm

• Niacin deficiency → pellagra

 

⭐ HARTNUP’S DISEASE

⭐ Definition

A hereditary defect of neutral amino acid transport in:

• Intestine

• Kidney proximal tubules

Neutral amino acids include:
Tryptophan, Alanine, Serine, Threonine, Valine, Leucine, Isoleucine, Phenylalanine, Tyrosine.

Tryptophan is the most clinically important.

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⭐ Biochemical Problem

• ↓ Absorption and reabsorption of neutral amino acids

• ↓ Tryptophan availability → ↓ Niacin synthesis

• Results in secondary pellagra-like syndrome

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⭐ Clinical Features

• Dermatitis (sun-exposed areas)

• Diarrhea

• Cerebellar ataxia

• Mood changes

• Intermittent episodes triggered by stress/infection

• Aminoaciduria (neutral amino acids)

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⭐ Investigations

• Elevated neutral amino acids in urine

• Low niacin deficiency markers

• Increased indican due to colonic bacterial conversion of unabsorbed tryptophan to indole

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⭐ Treatment

• High-protein diet

• Niacin/Nicotinamide supplementation

• Sun protection

• Avoid prolonged fasting and stress triggers

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⭐ PROLINE METABOLISM

⭐ Overview

Proline is a cyclic imino acid derived from glutamate.

⭐ Synthesis of Proline

Glutamate → Glutamate semialdehyde → Pyrroline-5-carboxylate → Proline

⭐ Functions

• Essential for collagen (gives tensile strength)

• Hydroxyproline helps stabilize collagen triple helix

• Important in wound healing

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⭐ HYDROXYPROLINE

⭐ Formation

Proline → Hydroxyproline

Enzyme: Prolyl hydroxylase
Cofactors: Vitamin C, Fe²⁺, α-ketoglutarate

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⭐ Clinical Significance

• Vitamin C deficiency → scurvy

  • Poor collagen hydroxylation

  • Bleeding gums, poor wound healing

  • Fragile capillaries

• Hydroxyproline is a major urinary marker of bone turnover.

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⭐ INTER-RELATION OF AMINO ACIDS

Amino acids interconvert through:

✔ Transamination

• Most amino acids ↔ glutamate

• ALT and AST use PLP (Vitamin B6)

✔ Deamination

• Removal of NH₂ for urea cycle (mainly via glutamate dehydrogenase)

✔ Amidation

• Glutamate → glutamine

• Aspartate → asparagine

✔ One-carbon transfers

• Serine ↔ glycine (THF + B6)

• Methionine ↔ homocysteine ↔ cysteine

• Tryptophan → formate → one-carbon pool

✔ Common metabolic intermediates

Many amino acids share key intermediates:

• Pyruvate: alanine, serine, cysteine, glycine

• Oxaloacetate: aspartate, asparagine

• α-Ketoglutarate: glutamate, glutamine, proline

• Fumarate: tyrosine, phenylalanine

• Succinyl-CoA: valine, isoleucine, methionine, threonine

This forms the metabolic basis for amino acids being:

• Glucogenic

• Ketogenic

• Or both

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⭐ AMINO ACIDURIAS (HIGH-YIELD OVERVIEW)

Disorders with abnormal urinary excretion of specific amino acids.

⭐ 1. Phenylketonuria (PKU)

• Phenylalanine hydroxylase defect

• Musty odor, intellectual disability

• ↑ Phenylalanine, phenylpyruvate

• Treat: Low Phe diet, tyrosine supplementation

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⭐ 2. Alkaptonuria

• Homogentisate oxidase defect

• Black urine, ochronosis, early arthritis

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⭐ 3. Albinism

• Tyrosinase defect → melanin absent

• Normal melanocyte number

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⭐ 4. Maple Syrup Urine Disease (MSUD)

• Branched-chain α-ketoacid dehydrogenase defect

• Maple-syrup odor, lethargy, seizures

• ↑ Leucine, isoleucine, valine

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⭐ 5. Cystinuria

• Renal transport defect of COLA amino acids

• Cystine stones (hexagonal crystals)

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⭐ 6. Homocystinuria

• CBS deficiency

• Downward lens dislocation, thrombosis, marfanoid habitus

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⭐ 7. Cystathioninuria

• Cystathionine γ-lyase defect

• Usually benign, B6 responsive

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⭐ 8. Hartnup’s Disease

• Neutral aminoaciduria, pellagra-like features

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⭐ 9. Tyrosinemias (Types I, II, III)

• Defects in downstream tyrosine metabolism

• Type I → severe liver failure

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⭐ 10. Indicanuria

• Excess indican excretion

• Seen in Hartnup disease, malabsorption

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⭐ Ultra-Short Revision

• Hartnup: neutral amino acids, pellagra-like, ↑ indican.

• Proline derived from glutamate; hydroxyproline needs vitamin C.

• Amino acids interconvert via transamination and one-carbon transfers.

• Amino acidurias = inherited defects in amino acid metabolism/transport (PKU, MSUD, cystinuria).

 

 

⭐ IMPORTANT POINTS TO REMEMBER (WHOLE CHAPTER)

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⭐ PHENYLALANINE & TYROSINE PATHWAYS

• Phenylalanine is essential; converted to tyrosine by phenylalanine hydroxylase (needs BH₄).

• Tyrosine becomes conditionally essential in PKU.

• Tyrosine is precursor for:

  • Melanin

  • Catecholamines (DOPA → dopamine → NE → epinephrine)

  • Thyroid hormones (T₃, T₄)

  • Fumarate + acetoacetate

• BH₄ deficiency can mimic classic PKU.

• Tyrosine degradation defects → alkaptonuria, tyrosinemias.

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⭐ MELANIN & ALBINISM

• Melanin formed from tyrosine → DOPA → dopaquinone.

• Tyrosinase (Cu-dependent) is key enzyme.

• Oculocutaneous albinism: Tyrosinase defect → absent melanin.

• Melanocyte number is normal, melanin formation is defective.

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⭐ CATECHOLAMINES

Pathway:
Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine

• Rate-limiting enzyme: Tyrosine hydroxylase.

• Dopamine β-hydroxylase requires Vitamin C + Copper.

• PNMT converts NE → E; requires SAM and induced by cortisol.

• Breakdown products:

  • NE/Epi → VMA

  • Dopamine → HVA

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⭐ PHENYLKETONURIA (PKU)

• Deficiency of phenylalanine hydroxylase or BH₄.

• ↑ Phenylalanine, ↓ tyrosine (becomes essential).

• Clinical: Musty odor, seizures, intellectual disability, pale skin.

• Treatment: Low Phe diet + tyrosine supplementation.

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⭐ ALKAPTONURIA

• Defect of homogentisate oxidase.

• Accumulation of homogentisic acid → black urine, ochronosis, early arthritis.

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⭐ TYROSINEMIAS (High-Yield Overview)

• Type I: Fumarylacetoacetate hydrolase defect → severe liver failure; cabbage-like odor.

• Type II: Tyrosine aminotransferase defect → keratitis, skin lesions.

• Type III: Hydroxyphenylpyruvate dioxygenase defect; neurological symptoms.

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⭐ TRYPTOPHAN METABOLISM

• Tryptophan is precursor of:

  • Serotonin

  • Melatonin

  • Niacin (requires B6, iron, riboflavin)

  • Kynurenine pathway intermediates

  • Indole → Indican

• 60 mg tryptophan → 1 mg niacin.

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⭐ SEROTONIN & MELATONIN

• Serotonin synthesized mainly in enterochromaffin cells.

• Carcinoid tumor diverts tryptophan → serotonin → 5-HIAA ↑.

• Serotonin → melatonin in pineal gland.

• Melatonin regulates sleep–wake cycle.

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⭐ NICOTINIC ACID (NIACIN) PATHWAY

• Derived from tryptophan via kynurenine pathway.

• Deficiency (pellagra) seen in:

  • Hartnup disease

  • Carcinoid syndrome

  • Isoniazid therapy (B6 deficiency)

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⭐ INDICAN

• Gut bacteria convert tryptophan → indole → liver converts to indoxyl sulfate (Indican).

• Excess indican seen in:

  • Hartnup disease

  • Malabsorption

  • Bacterial overgrowth.

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⭐ HARTNUP’S DISEASE

• Defective transport of neutral amino acids (especially tryptophan).

• Features: Pellagra-like dermatitis, ataxia, aminoaciduria.

• ↑ Indican due to bacterial metabolism of unabsorbed tryptophan.

• Treat: High-protein diet + niacin.

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⭐ PROLINE & HYDROXYPROLINE

• Proline synthesized from glutamate.

• Hydroxyproline formed by prolyl hydroxylase (needs Vitamin C).

• Hydroxyproline stabilizes collagen triple helix.

• Vitamin C deficiency → scurvy (poor collagen stability).

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⭐ AMINO ACIDURIAS (HIGH-YIELD LIST)

• PKU (phenylalanine hydroxylase defect)

• Alkaptonuria (homogentisate oxidase)

• Cystinuria (COLA transport defect)

• Hartnup disease (neutral AA transport defect)

• Homocystinuria (CBS defect)

• Tyrosinemias (I, II, III)

• MSUD (BCKD defect)

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⭐ Ultra-Short Revision for Exams

• Phenylalanine → Tyrosine (BH₄ required).

• Tyrosine makes melanin, catecholamines, thyroid hormones.

• PKU = high phenylalanine + low tyrosine + musty odor.

• Alkaptonuria = black urine + ochronosis.

• Albinism = tyrosinase defect.

• Tryptophan makes serotonin, melatonin, niacin.

• Carcinoid = serotonin ↑, niacin ↓, 5-HIAA ↑.

• Hartnup = neutral aminoaciduria + pellagra-like.

• Proline/hydroxyproline essential for collagen (needs vitamin C).

 

⭐ CLINICAL CASE–BASED QUESTIONS

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⭐ 1. Infant with Musty Odor + Seizures + Fair Skin

A 3-month-old infant presents with developmental delay, seizures, and pale skin and hair. Parents report a “musty/mousy” odor.
Blood analysis shows very high phenylalanine and low tyrosine.

Diagnosis:

Phenylketonuria (PKU)

Clue Summary:

• Musty odor → phenylacetate

• ↓ tyrosine → hypopigmentation

• Progressive intellectual disability if untreated

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⭐ 2. Teenager with Black Urine on Standing

A 17-year-old boy notices that his urine turns black when left standing.
He has chronic back pain and pigmentation of ear cartilage.

Diagnosis:

Alkaptonuria

Key Findings:

• Homogentisate oxidase defect

• Ochronosis

• Early osteoarthritis

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⭐ 3. Child with White Hair, Photophobia, and Normal Melanocyte Count

A 4-year-old child has very light skin, white hair, nystagmus, and severe visual impairment.
Melanocyte count in skin biopsy is normal, but melanin is absent.

Diagnosis:

Oculocutaneous Albinism (Tyrosinase deficiency)

Important:

• Melanocyte number normal

• Tyrosine → melanin conversion blocked

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⭐ 4. Infant with Liver Failure + Cabbage-Like Odor

A 6-month-old child presents with failure to thrive, jaundice, renal tubular acidosis, and a characteristic cabbage-like odor.
Plasma tyrosine is very high.

Diagnosis:

Tyrosinemia Type I

Reason:

• Fumarylacetoacetate hydrolase defect

• Severe liver/kidney involvement

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⭐ 5. Child with Skin Lesions + Corneal Ulcers + High Tyrosine

A 2-year-old has painful corneal erosions, thickened skin on palms/soles, and high serum tyrosine.

Diagnosis:

Tyrosinemia Type II

“Richner–Hanhart syndrome.”

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⭐ 6. Young Adult with Episodic Ataxia + Pellagra-Like Rash

A 20-year-old presents with intermittent ataxia, psychiatric symptoms, and photosensitive dermatitis.
Urine analysis: Elevated neutral amino acids.
Increased indican.

Diagnosis:

Hartnup Disease

Explanation:

• ↓ Tryptophan absorption → ↓ Niacin → Pellagra-like symptoms

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⭐ 7. Patient with Severe Flushing + Diarrhea + Wheezing

A 35-year-old patient presents with episodic flushing, diarrhea, and wheezing.
Urinary 5-HIAA is massively elevated.

Diagnosis:

Carcinoid Syndrome

Key Biochemistry:

• Excess serotonin formation

• Tryptophan diverted → ↓ niacin → pellagra risk

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⭐ 8. Night-Shift Worker with Sleep Disturbance

A software engineer who works night shifts complains of poor sleep regulation.
Melatonin level is low.

Diagnosis:

Melatonin deficiency due to circadian disruption

Biochemical Link:

• Serotonin → melatonin (pineal gland)

• Pathway dependent on darkness and suprachiasmatic nucleus signaling

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⭐ 9. Child with Blue Diaper Syndrome

A baby’s diaper turns blue after exposure to air.
Urinary indican is very high.

Diagnosis:

Indicanuria (seen in Hartnup disease/malabsorption)

Reason:

• Tryptophan → indole (gut bacteria) → oxidized to blue pigments

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⭐ 10. Osteoarthritis in a 35-Year-Old with “Black Ear”

A man in his mid-30s has progressive joint pain.
Ear cartilage appears bluish-black.

Diagnosis:

Alkaptonuria

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⭐ 11. Neonate with Persistent Vomiting + Musty Odor After Breastfeeding

Newborn becomes irritable and vomits after feeds.
Musty smell noted.
Phenylalanine is very high.

Diagnosis:

Classic PKU

Importance:

Newborn screening prevents neurological damage.

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⭐ 12. Patient with Anxiety + Sweating + High VMA

A 40-year-old woman has episodes of palpitations, sweating, and tremors.
Urine VMA is high.

Diagnosis:

Pheochromocytoma

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⭐ 13. Toddler with Brittle Hair + Poor Growth + Low Niacin

A 3-year-old child has alopecia, dermatitis, and diarrhea.
Niacin levels are low.
Carcinoid syndrome is ruled out.

Diagnosis:

Hartnup Disease (tryptophan malabsorption → niacin deficiency)

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⭐ 14. Man with Depression + Low Serotonin + High Kynurenine

A 28-year-old man has chronic depression.
Biochemical testing reveals low serotonin, but normal tryptophan.

Diagnosis:

Increased diversion of tryptophan into kynurenine pathway
(seen in chronic inflammation or vitamin B6 deficiency)

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⭐ 15. Infant with Severe Photosensitivity + High Tyrosine

Non-healing corneal ulcers + painful keratoconjunctivitis + palmoplantar hyperkeratosis.

Diagnosis:

Tyrosinemia Type II

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⭐ 16. Man with Low Melatonin + High Cortisol

A stressed executive shows insomnia and altered sleep-wake cycle.

Biochemical Insight:

Cortisol suppresses melatonin synthesis in the pineal gland.

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⭐ 17. Elderly Woman with Progressive Joint Degeneration + Urine Turns Brown

She complains of dark urine on standing and chronic arthritis.

Diagnosis:

Alkaptonuria

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⭐ 18. Infant on Soy Milk Diet Developing Dermatologic Symptoms

Soy diet → low tryptophan → niacin deficiency symptoms.

Diagnosis:

Secondary pellagra due to tryptophan deficiency.

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⭐ 19. Schizophrenia Patient with High Kynurenic Acid

Kynurenine pathway imbalance contributes to neurotoxicity/neuropsychiatric symptoms.

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⭐ 20. Teenager with Normal Phenylalanine Levels but PKU-like Symptoms

Likely BH₄ deficiency, not enzyme defect.

 

 

 

⭐ MCQs — Whole Chapter

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1. Phenylalanine → Tyrosine requires which cofactor?

A. FAD
B. NADPH
C. PLP
D. BH₄

Answer: D

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2. Tyrosine becomes essential in which disorder?

A. Alkaptonuria
B. Homocystinuria
C. PKU
D. Hartnup disease

Answer: C

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3. The enzyme deficient in alkaptonuria is:

A. Fumarylacetoacetate hydrolase
B. Homogentisate oxidase
C. Tyrosine aminotransferase
D. Tyrosinase

Answer: B

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4. A patient’s urine turns black after standing. Most likely diagnosis:

A. MSUD
B. PKU
C. Alkaptonuria
D. Hartnup disease

Answer: C

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5. Tyrosinase is required for synthesis of:

A. Dopamine
B. Melatonin
C. Melanin
D. Indican

Answer: C

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6. Which amino acid is precursor of catecholamines?

A. Tryptophan
B. Glycine
C. Tyrosine
D. Serine

Answer: C

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7. The rate-limiting enzyme in catecholamine synthesis is:

A. DOPA decarboxylase
B. PNMT
C. Dopamine β-hydroxylase
D. Tyrosine hydroxylase

Answer: D

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8. Norepinephrine → Epinephrine conversion requires:

A. Vitamin C
B. Biotin
C. SAM
D. B12

Answer: C

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9. Elevated VMA in urine indicates overproduction of:

A. Serotonin
B. Norepinephrine/Epinephrine
C. Dopamine
D. Melanin

Answer: B

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10. Melatonin is synthesized in which organ?

A. Hypothalamus
B. Liver
C. Thyroid
D. Pineal gland

Answer: D

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11. Tryptophan → Serotonin requires which cofactor?

A. Biotin
B. B12
C. BH₄
D. Vitamin C

Answer: C

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12. Carcinoid tumor causes deficiency of:

A. Vitamin C
B. Niacin
C. B12
D. Biotin

Answer: B

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13. Niacin synthesis from tryptophan requires:

A. Folic acid
B. Vitamin K
C. Vitamin B6
D. Vitamin D

Answer: C

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14. Pellagra-like symptoms + neutral aminoaciduria suggests:

A. MSUD
B. PKU
C. Hartnup disease
D. Cystinuria

Answer: C

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15. Excess indican in urine is seen in:

A. PKU
B. Hartnup disease
C. Alkaptonuria
D. MSUD

Answer: B

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16. Which metabolite causes black urine in alkaptonuria?

A. Dopamine
B. Serotonin
C. Homogentisic acid
D. Indole

Answer: C

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17. Melatonin is synthesized from:

A. Tyrosine
B. Alanine
C. Serotonin
D. Tryptophan only

Answer: C

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18. A patient with “musty odor” most likely has defect in:

A. Homogentisate oxidase
B. Tyrosinase
C. Phenylalanine hydroxylase
D. MAO

Answer: C

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19. High 5-HIAA in urine indicates:

A. PKU
B. Tyrosinemia
C. Carcinoid syndrome
D. Alkaptonuria

Answer: C

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20. Vitamin C is cofactor for which catecholamine step?

A. Tyrosine → DOPA
B. DOPA → Dopamine
C. Dopamine → Norepinephrine
D. Norepinephrine → Epinephrine

Answer: C

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21. Trytophan is BOTH glucogenic and ketogenic. Which products form these pathways?

A. Succinate & Fumarate
B. Alanine & Acetyl-CoA
C. Pyruvate & Propionate
D. Acetoacetate & Citrate

Answer: B

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22. Which disorder shows ochronosis?

A. PKU
B. Hartnup disease
C. MSUD
D. Alkaptonuria

Answer: D

---

23. Which hormone induces PNMT enzyme?

A. TSH
B. Insulin
C. GH
D. Cortisol

Answer: D

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24. Requirements for proline hydroxylation are:

A. B12 + Mg²⁺
B. Vitamin C + Fe²⁺
C. Biotin + ATP
D. FAD + NADH

Answer: B

---

25. Blue diaper syndrome is due to excess:

A. VMA
B. Phenylacetate
C. Indican
D. HVA

Answer: C

---

26. A baby with cataracts + skin lesions + high tyrosine likely has:

A. Hartnup disease
B. PKU
C. Tyrosinemia Type II
D. MSUD

Answer: C

---

27. Which of the following becomes essential in PKU?

A. Valine
B. Leucine
C. Tyrosine
D. Serine

Answer: C

---

28. A lab report shows high HVA in urine. This indicates excess breakdown of:

A. Serotonin
B. Dopamine
C. Tyrosine
D. Tryptophan

Answer: B

---

29. The first step in melanin synthesis is:

A. Tyrosine → Dopamine
B. Tyrosine → Indole
C. Tyrosine → DOPA
D. DOPA → Epinephrine

Answer: C

---

30. A patient with insomnia + low melatonin likely has decreased activity of:

A. Tyrosine hydroxylase
B. Hydroxy-indole-O-methyltransferase
C. MAO
D. COMT

Answer: B

 

 

⭐ VIVA VOCE – AROMATIC AMINO ACIDS & AMINO ACIDURIAS

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1. What is the precursor of tyrosine?

Phenylalanine.

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2. Which cofactor is required for conversion of phenylalanine → tyrosine?

BH₄ (Tetrahydrobiopterin).

---

3. What happens to tyrosine in PKU?

It becomes essential, because its synthesis from phenylalanine is blocked.

---

4. Name two hormones formed from tyrosine.

Thyroxine (T₄) and epinephrine.

---

5. What is the rate-limiting step of catecholamine synthesis?

Tyrosine → DOPA via tyrosine hydroxylase.

---

6. Which enzyme converts dopamine → norepinephrine?

Dopamine β-hydroxylase.

---

7. Which cofactor does dopamine β-hydroxylase require?

Vitamin C (and copper).

---

8. What converts norepinephrine → epinephrine?

PNMT (Phenylethanolamine N-methyltransferase).

---

9. Which hormone induces PNMT?

Cortisol.

---

10. What is the breakdown product of dopamine?

HVA (Homovanillic acid).

---

11. What is the breakdown product of norepinephrine/epinephrine?

VMA (Vanillylmandelic acid).

---

12. Tyrosinase deficiency leads to which condition?

Albinism.

---

13. Is melanocyte number normal in albinism?

Yes. The defect is in melanin synthesis, not melanocyte count.

---

14. What gives the musty odor in PKU?

Phenylacetate.

---

15. Which enzyme is defective in alkaptonuria?

Homogentisate oxidase.

---

16. What is ochronosis?

Bluish-black pigmentation of cartilage seen in alkaptonuria.

---

17. Which amino acid produces serotonin?

Tryptophan.

---

18. Which cofactor is required for serotonin synthesis?

BH₄ for tryptophan hydroxylase, and PLP for decarboxylation.

---

19. Where is most serotonin produced?

Enterochromaffin cells of intestine.

---

20. What is the urinary marker for serotonin excess?

5-HIAA.

---

21. What disorder produces high 5-HIAA levels?

Carcinoid syndrome.

---

22. Melatonin is synthesized from which compound?

Serotonin.

---

23. Where is melatonin produced?

Pineal gland.

---

24. Tryptophan forms which vitamin?

Niacin (Vitamin B₃).

---

25. Niacin synthesis from tryptophan requires which vitamin?

Vitamin B6.

---

26. What is the classic triad of pellagra?

Dermatitis, diarrhea, dementia.

---

27. Which disorder mimics pellagra due to tryptophan deficiency?

Hartnup disease.

---

28. What is the defect in Hartnup disease?

Defective transport of neutral amino acids (including tryptophan).

---

29. Why is indican increased in Hartnup disease?

Unabsorbed tryptophan → converted to indole → indican.

---

30. What causes blue diaper syndrome?

Excess indican oxidizing in the diaper.

---

31. Name the enzyme involved in hydroxylation of proline.

Prolyl hydroxylase.

---

32. Which vitamin is required for proline and lysine hydroxylation?

Vitamin C.

---

33. What happens to collagen when vitamin C is deficient?

Poor hydroxylation → scurvy (bleeding, poor wound healing).

---

34. Which tyrosinemia presents with cabbage-like odor?

Tyrosinemia Type I.

---

35. Which tyrosinemia presents with corneal ulcers?

Tyrosinemia Type II.

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36. What is the major product of catecholamine breakdown in neuroblastoma?

HVA.

---

37. What disorder shows black urine on standing?

Alkaptonuria.

---

38. Why does alkaptonuric urine turn black only after standing?

Homogentisic acid oxidizes in air.

---

39. What is the amino acid precursor for thyroid hormones?

Tyrosine.

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40. What causes neurological damage in PKU?

Accumulated phenylalanine interferes with brain myelination.