SN3 SHORT NOTE 5M ★ High-yield

Describe allosteric enzymes with their characteristics and examples. Add a note on feedback inhibition.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Allosteric enzymes = regulatory enzymes whose activity is altered by the non-covalent binding of a modulator at a site other than the active site.

Usually the rate-limiting enzyme of a pathway, catalysing the first committed and irreversible step

Characteristics

Oligomeric — several subunits, each with an active site and a regulatory (allosteric) site
Sigmoid (S-shaped) kinetics, not the hyperbola of Michaelis–Menten
Show co-operativity — binding at one site changes the affinity of the others
The measure of affinity is K0.5, not Km
Sensitive to small changes in modulator concentration — the sigmoid shape means a small rise produces a large change in rate
Modulators may be homotropic (the substrate itself) or heterotropic (a different molecule)

Models of Allosteric Behaviour

Model	Proposed by	Concept
Concerted (symmetry)	Monod, Wyman, Changeux	All subunits switch together between a T (tense, low affinity) and R (relaxed, high affinity) state
Sequential	Koshland	Subunits change one at a time, each influencing the next

Important Examples

Enzyme	Pathway	Positive modulator	Negative modulator
Phosphofructokinase-1	Glycolysis	Amp, fructose-2,6-bisphosphate	ATP, citrate
Aspartate transcarbamoylase	Pyrimidine synthesis	ATP	CTP (feedback)
Isocitrate dehydrogenase	TCA cycle	ADP	ATP, NADH
HMG-CoA reductase	Cholesterol synthesis	—	Cholesterol
Carbamoyl phosphate synthetase I	Urea cycle	N-acetylglutamate	—
Acetyl-CoA carboxylase	Fatty acid synthesis	Citrate	Palmitoyl-CoA

Feedback Inhibition

A → Enzyme 1 (allosteric, rate-limiting) → B → C → End product D → D inhibits Enzyme 1

Also called end-product or retro-inhibition
Prevents wasteful overproduction — the commonest physiological control of a pathway
Acts on the first committed step, so no intermediates accumulate

Applied Aspects

Haemoglobin is the classic allosteric protein — sigmoid oxygen curve, T and R states, with 2,3-BPG, H+ and CO2 as negative modulators. It is not an enzyme but obeys the same principles
Allosteric drugs — benzodiazepines act at an allosteric site on the GABAA receptor
Loss of feedback inhibition underlies some metabolic disease — in acute intermittent porphyria, reduced haem fails to inhibit ala synthase, so precursors accumulate

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