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BI5.1-9 | Chemistry & Metabolism of Proteins and Immunology — Part 3

Specialised Products from Amino Acids and Inborn Errors (BI5.7)

Amino acids are not just protein building blocks — they are precursors for some of the body's most important molecules. When the enzymes that process them are missing, the consequences are devastating.

Figure: Specialised Products from Amino Acids and Inborn Errors (BI5.7)

Glycine — the simplest amino acid (R-group is just H):
- Precursor for: haem (we'll cover this next), purines (DNA building blocks), creatine (muscle energy reserve), glutathione (antioxidant), bile salts (conjugation)
- Glycine is also an inhibitory neurotransmitter in the spinal cord

Phenylalanine and Tyrosine:
- Phenylalanine → tyrosine (by phenylalanine hydroxylase, requires BH4 cofactor)
- Tyrosine is the precursor for: catecholamines (dopamine → noradrenaline → adrenaline), thyroid hormones (T3, T4), melanin (skin/hair pigment)
- Phenylketonuria (PKU) — deficiency of phenylalanine hydroxylase → Phe accumulates → musty/mousy odour in urine, intellectual disability if untreated. Detected by Guthrie test (newborn screening). Treatment: low-Phe diet from birth + tyrosine supplementation.
- Alkaptonuria — deficiency of homogentisic acid oxidase (in tyrosine degradation) → homogentisic acid accumulates → urine turns dark on standing (ochronosis), dark pigment deposits in cartilage. Relatively benign.
- Albinism — deficiency of tyrosinase → no melanin → white skin/hair, pink eyes, photosensitivity

Tryptophan:
- Precursor for: serotonin (mood neurotransmitter) → melatonin (sleep hormone), and NAD+/NADP+ (niacin — vitamin B3)
- Carcinoid syndrome — tryptophan is diverted to serotonin by the tumour → niacin deficiency → pellagra (dermatitis, diarrhoea, dementia)
- Hartnup disease — poor tryptophan absorption → pellagra-like symptoms

Methionine:
- Activated form is S-adenosylmethionine (SAM) — the body's universal methyl donor (methylation of DNA, RNA, proteins, phospholipids, neurotransmitters)
- Homocystinuria — deficiency of cystathionine beta-synthase → homocysteine accumulates → tall stature, lens subluxation (downward, unlike Marfan which is upward), intellectual disability, thromboembolism

Branched-chain amino acids (Val, Leu, Ile):
- Maple syrup urine disease (MSUD) — deficiency of branched-chain alpha-keto acid dehydrogenase → branched-chain amino acids and their keto acids accumulate → sweet-smelling urine, neurological damage, lethal if untreated

Newborn screening — most countries now screen for PKU, MSUD, homocystinuria, and other inborn errors using a heel-prick blood sample taken 48-72 hours after birth (tandem mass spectrometry). Early detection and dietary management prevent irreversible brain damage.

Haem — Structure, Synthesis and Degradation (BI5.8)

Haem is a flat, ring-shaped molecule made of four pyrrole rings joined together (porphyrin ring) with an iron atom (Fe2+) at the centre. It is the prosthetic group of haemoglobin, myoglobin, cytochromes, catalase, and peroxidase.

Figure: Haem — Structure, Synthesis and Degradation (BI5.8)

Haem synthesis (occurs in bone marrow and liver):
The pathway starts in the mitochondria, moves to the cytoplasm, and returns to the mitochondria:

1. Succinyl-CoA + Glycine → delta-aminolevulinic acid (ALA) — catalysed by ALA synthase (rate-limiting step, mitochondria). Requires pyridoxal phosphate (vitamin B6) as cofactor. Inhibited by haem (feedback inhibition).
2. 2 ALA → porphobilinogen (PBG) — catalysed by ALA dehydratase (cytoplasm). Inhibited by lead (this is why lead poisoning causes anaemia).
3. PBG → ... → protoporphyrin IX (through several intermediates in cytoplasm)
4. Protoporphyrin IX + Fe2+ → haem — catalysed by ferrochelatase (mitochondria). Also inhibited by lead.

Haem degradation (produces bilirubin → jaundice):

1. Old RBCs are destroyed in the reticuloendothelial system (spleen, liver, bone marrow)
2. Haem → biliverdin (green) → unconjugated bilirubin (yellow, lipid-soluble, toxic) — carried in blood bound to albumin
3. Liver takes up unconjugated bilirubin → conjugated with glucuronic acid by UDP-glucuronyl transferase → conjugated bilirubin (water-soluble, non-toxic)
4. Conjugated bilirubin is secreted into bile → reaches the intestine
5. Gut bacteria convert it to urobilinogen → most is excreted as stercobilinogen/stercobilin (gives faeces their brown colour)
6. Some urobilinogen is reabsorbed (enterohepatic circulation) → part is re-excreted by the liver, part goes to the kidney → urobilin (gives urine its yellow colour)

Types of jaundice:
- Pre-hepatic (haemolytic): excessive RBC destruction → unconjugated bilirubin rises → dark urine (urobilinogen), dark stools (excess stercobilin)
- Hepatic (hepatocellular): liver damage → both conjugated and unconjugated bilirubin rise
- Post-hepatic (obstructive): bile duct blocked → conjugated bilirubin rises → dark urine (conjugated bilirubin in urine), pale/clay-coloured stools (no stercobilin)

Neonatal jaundice — physiological jaundice in newborns occurs because the immature liver has low UDP-glucuronyl transferase activity. Usually resolves by day 10. If unconjugated bilirubin rises too high, it crosses the blood-brain barrier → kernicterus (bilirubin encephalopathy) → permanent brain damage. Treatment: phototherapy (blue light converts bilirubin to a water-soluble form that can be excreted without conjugation).

Porphyrias — inherited defects in haem synthesis enzymes → accumulation of porphyrin intermediates:
- Acute intermittent porphyria — defect in PBG deaminase → ALA and PBG accumulate → abdominal pain, neuropsychiatric symptoms, dark urine (porphyrin oxidation). Triggered by drugs (barbiturates, alcohol) that induce ALA synthase.
- Porphyria cutanea tarda — most common porphyria → photosensitive skin blisters (porphyrins absorb light and generate free radicals)

Haemoglobin — Types, Derivatives and Variants (BI5.9)

Haemoglobin (Hb) is the oxygen-carrying protein in red blood cells. Each molecule is a tetramer — 4 globin subunits, each carrying one haem group. So one Hb molecule carries up to 4 oxygen molecules.

Figure: Haemoglobin — Types, Derivatives and Variants (BI5.9)

Normal haemoglobin types:
- HbA (α2β2) — the major adult haemoglobin (~97% of adult Hb). Two alpha chains + two beta chains.
- HbA2 (α2δ2) — minor adult haemoglobin (~2-3%). Two alpha + two delta chains. Elevated in beta-thalassaemia trait (because beta chain production is reduced, delta chains compensate).
- HbF (α2γ2) — foetal haemoglobin (~60-80% at birth, falls to <1% by 6 months). Two alpha + two gamma chains. HbF has higher oxygen affinity than HbA — it snatches oxygen from maternal blood across the placenta. This is because HbF binds 2,3-bisphosphoglycerate (2,3-BPG) less effectively than HbA.

Haemoglobin derivatives:
- Oxyhaemoglobin (HbO2) — Hb bound to oxygen (bright red, in arterial blood)
- Deoxyhaemoglobin (deoxy-Hb) — Hb without oxygen (dark red/blue, in venous blood — this is why veins look blue through the skin)
- Carboxyhaemoglobin (HbCO) — Hb bound to carbon monoxide. CO has 250x greater affinity for Hb than O2 → even small amounts of CO displace O2 → tissue hypoxia. The patient looks cherry-red (not cyanotic), which is deceptive. Diagnosis: CO-oximetry (not pulse oximetry, which reads HbCO as HbO2). Treatment: 100% oxygen.
- Methaemoglobin (MetHb) — iron in haem is oxidised from Fe2+ to Fe3+ → cannot carry oxygen. Causes: nitrates/nitrites, dapsone, aniline dyes. Patients appear chocolate-brown cyanosis that does not respond to oxygen. Treatment: methylene blue IV (reduces Fe3+ back to Fe2+).
- Glycosylated haemoglobin (HbA1c) — glucose attaches non-enzymatically to the N-terminal valine of the beta chain. HbA1c reflects average blood glucose over 2-3 months (lifespan of RBC). Target in diabetes: <7%. Used for monitoring, NOT diagnosis in India (HbS and HbE interfere with some assays).

Haemoglobin variants (haemoglobinopathies):
- HbS (sickle haemoglobin) — point mutation: beta-6 Glu→Val. In deoxygenated state, HbS polymerises → sickle-shaped RBCs → vaso-occlusion (painful crises), haemolysis, organ damage. Heterozygotes (HbAS, sickle trait) are protected against falciparum malaria — this is why the sickle gene persists in malaria-endemic regions.
- HbC — beta-6 Glu→Lys. Milder than HbS. Target cells on blood film.
- HbE — beta-26 Glu→Lys. Common in Southeast Asia and northeast India. Usually mild. HbE/beta-thalassaemia is severe.

Thalassaemias — reduced production (not abnormal structure) of globin chains:
- Alpha-thalassaemia — reduced/absent alpha-chain synthesis. Four alpha genes (2 per chromosome 16). One deletion = silent carrier, two = alpha-thal trait, three = HbH disease (β4 tetramers), four = Hb Bart's (γ4 tetramers) → hydrops fetalis (fatal in utero).
- Beta-thalassaemia — reduced/absent beta-chain synthesis. Two beta genes (1 per chromosome 11). Beta-thal trait (minor) = one gene affected → mild microcytic anaemia, elevated HbA2. Beta-thal major (Cooley's anaemia) = both genes affected → severe anaemia from 6 months (when HbF should switch to HbA), transfusion-dependent, iron overload, bone marrow expansion (crew-cut skull on X-ray).

Spiral forward: In Physiology, you're learning about the oxygen dissociation curve — the sigmoid curve of HbA, left-shifted HbF, and how 2,3-BPG, pH, temperature, and CO2 shift the curve. The biochemistry you learn here (subunit structure, cooperativity, HbF affinity) is the molecular explanation for everything you see on that curve.