Proteins
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Direct answer
Protein function follows from structure: the amino acid sequence (primary) folds into α-helices and β-pleated sheets (secondary), packs into a three-dimensional shape (tertiary) and, in multi-chain proteins such as haemoglobin, assembles into a quaternary structure. Haemoglobin, the most examined protein in FMGE Biochemistry, is an α2β2 tetramer whose sigmoid oxygen-dissociation curve reflects cooperativity between subunits — shifted right by hydrogen ions, carbon dioxide, temperature and 2,3-bisphosphoglycerate (the Bohr effect), and shifted left by carbon monoxide, foetal haemoglobin and methaemoglobin. Collagen, the other examination favourite, is a triple helix in which every third residue must be glycine, with hydroxyproline formation dependent on vitamin C — the biochemical basis of scurvy.
What you must remember
- The α-helix has 3.6 residues per turn stabilised by intrachain hydrogen bonds; haemoglobin is largely helical, while β-pleated sheets dominate immunoglobulin domains and silk.
- Myoglobin, a single-chain muscle protein, gives a hyperbolic curve with a P50 near 1 mmHg; adult haemoglobin has a P50 of about 26–27 mmHg — myoglobin stores oxygen, haemoglobin transports it.
- Right shifts (better unloading): hydrogen ion, carbon dioxide, fever, exercise, altitude, 2,3-BPG. Left shifts: carbon monoxide, methaemoglobinaemia, HbF (γ chains bind 2,3-BPG poorly), alkalosis, hypothermia.
- HbA1c forms by non-enzymatic glycation of the β-chain N-terminal valine and tracks the average glucose of the preceding 8–12 weeks (erythrocyte lifespan 120 days); 6.5% or above supports a diagnosis of diabetes.
- Sickle haemoglobin (glutamate to valine at β6, a missense point mutation) polymerises when deoxygenated; sickle-cell trait protects against severe falciparum malaria, which explains the gene's frequency in central Indian and tribal populations.
- Collagen: Gly-X-Y repeat with hydroxylation of proline and lysine requiring vitamin C, and crosslinking by copper-dependent lysyl oxidase; type I bone and skin, type II cartilage, type III blood vessels (vascular Ehlers–Danlos), type IV basement membrane (Goodpasture, Alport).
- Albumin, about 60% of plasma protein, maintains oncotic pressure and carries bilirubin, calcium, free fatty acids and warfarin; its roughly 20-day half-life makes it a slow index of liver synthesis.
- α1-antitrypsin deficiency (PiZZ) causes panacinar emphysema and cirrhosis with periodic-acid-Schiff-positive hepatocyte globules; smoking accelerates the lung destruction.
How to reason through a misleading pulse oximeter
A survivor pulled from a house fire is drowsy with cherry-red lips; the pulse oximeter reads 99% while the patient worsens. Work the chemistry: carboxyhaemoglobin absorbs almost the same two wavelengths as oxyhaemoglobin, so a conventional pulse oximeter cannot tell them apart and overestimates true saturation. The arterial PaO2, which measures dissolved oxygen, is genuinely normal, because carbon monoxide acts on haemoglobin binding rather than on alveolar delivery — a normal blood gas does not clear the patient. Carbon monoxide binds haemoglobin with roughly 240 times the affinity of oxygen and shifts the curve left, so the oxygen that is bound is held back from tissues. Treatment is 100% oxygen, which shortens the carboxyhaemoglobin half-life from about 4–5 hours on room air to about 60 minutes, with hyperbaric oxygen reserved for neurological deficits, coma or pregnancy. The same reasoning explains chronic smokers walking around with carboxyhaemoglobin levels of 8–10% and a left-shifted curve.
Where students slip
Curve directions get reversed under pressure, so anchor the physiology: a metabolising tissue that is acid, hot and carbon-dioxide-rich deserves oxygen, hence the right shift. Second, myoglobin's hyperbola is mistaken for haemoglobin's sigmoid — one binding site cannot be cooperative. Third, HbA1c is quoted without its caveats: it runs falsely low in haemolysis and wrongly high in iron deficiency, and it is unreliable in thalassaemia trait and other haemoglobinopathies, which matter in India; use glucose criteria in those patients. Fourth, the sickle mutation is a missense substitution, not a frameshift, and electrophoresis at alkaline pH moves HbS more slowly than HbA toward the anode because the mutation deletes a negative charge. Fifth, vitamin C is a cofactor for prolyl hydroxylase, not a constituent of collagen itself — the unstable triple helix of scurvy is the consequence.
Frequently asked questions
Which compound shifts the oxygen dissociation curve right, and why does it rise at altitude?
2,3-bisphosphoglycerate, made in the Rapoport–Luebering shunt of the erythrocyte; chronic hypoxia raises it, improving unloading to tissues.
Why is foetal haemoglobin left shifted?
Its γ chains bind 2,3-BPG poorly, raising affinity so the foetus pulls oxygen across the placenta; this is also why HbF persistence softens sickle-cell disease.
What is the mutation and mutation type in sickle-cell anaemia?
A GAG to GTG transversion at β codon 6 replaces glutamate with valine — a missense mutation that lets deoxygenated haemoglobin polymerise.
Why can HbA1c mislead, and in which Indian-relevant conditions?
It is falsely low in haemolysis or shorter erythrocyte lifespan and falsely high in iron deficiency; haemoglobinopathies such as thalassaemia trait invalidate the assay.
Which plasma protein carries unconjugated bilirubin, and what is the clinical consequence?
Albumin; sulphonamides and other competitive binders displace bilirubin in neonates, raising the risk of kernicterus.
Which protein deficiency causes both emphysema and cirrhosis?
α1-antitrypsin deficiency, in which misfolded PiZZ protein accumulates in hepatocytes while unopposed elastase destroys lung alveoli.