Q4 LONG ANSWER 10M ★ High-yield

Describe the mechanisms regulating enzyme activity. Explain allosteric regulation, covalent modification and enzyme induction with examples.

Biochemistry · 1st Professional — Pre-Clinical

WHY Regulation Is Needed

Metabolic pathways must respond to changing demand. Regulation acts at the rate-limiting (committed) step, which is usually an irreversible reaction catalysed by an allosteric enzyme.

Mechanisms — Overview

Mechanism	Speed	Changes
Allosteric regulation	Seconds	Activity of existing enzyme
Covalent modification	Seconds to minutes	Activity of existing enzyme
Proteolytic activation of zymogens	Minutes	Irreversible activation
Induction and repression	Hours to days	Amount of enzyme
Compartmentation	—	Access to substrate
Isoenzymes	—	Tissue-appropriate kinetics

Allosteric Regulation

The regulator binds at a site distinct from the active site (Greek allos = other)
Positive modulator → increases activity; negative modulator → decreases it
Allosteric enzymes are oligomeric and show sigmoid kinetics
Feedback (end-product) inhibition is the commonest form — the final product of a pathway inhibits the first committed enzyme

Enzyme	Activator	Inhibitor
Phosphofructokinase-1	Amp, ADP, fructose-2,6-bisphosphate	ATP, citrate, H+
Isocitrate dehydrogenase	ADP, Ca2+	ATP, NADH
Acetyl-CoA carboxylase	Citrate	Palmitoyl-CoA
Pyruvate carboxylase	Acetyl-CoA	ADP
HMG-CoA reductase	—	Cholesterol
Ala synthase	—	Haem

Covalent Modification

The commonest is phosphorylation and dephosphorylation
Protein kinases phosphorylate (using ATP) at serine, threonine or tyrosine; phosphatases remove it
Ultimately controlled by hormones through second messengers

Glucagon / adrenaline → ↑ cAMP → Protein kinase A → Phosphorylates target enzymes → Glycogen phosphorylase activated; glycogen synthase inactivated

Enzyme	Phosphorylated form
Glycogen phosphorylase	Active
Glycogen synthase	Inactive
Pyruvate dehydrogenase	Inactive
Hormone-sensitive lipase	Active
Acetyl-CoA carboxylase	Inactive
HMG-CoA reductase	Inactive

CLINICAL PEARL

The pattern is consistent: phosphorylation (the fasting, glucagon-driven state) switches ON the pathways that release fuel and switches off those that store it. Insulin, by promoting dephosphorylation, does the reverse.

Zymogens (proenzymes)

Inactive precursors activated by irreversible proteolytic cleavage
Purpose — prevents the enzyme digesting the cell that makes it, and allows a rapid, amplifying response

Zymogen	Active enzyme	Activated by
Trypsinogen	Trypsin	Enterokinase, then trypsin itself
Chymotrypsinogen	Chymotrypsin	Trypsin
Pepsinogen	Pepsin	HCl, then pepsin (autocatalysis)
Prothrombin	Thrombin	Prothrombin activator
Procarboxypeptidase	Carboxypeptidase	Trypsin
Plasminogen	Plasmin	TPA, urokinase, streptokinase

Induction and Repression

Alters the amount of enzyme by changing the rate of transcription; slow but long lasting
Inducible enzymes — glucokinase, HMG-CoA reductase, ala synthase, the urea cycle enzymes, cytochrome P450
Insulin induces glucokinase and the lipogenic enzymes; glucagon and cortisol induce the gluconeogenic enzymes
Constitutive enzymes are produced at a constant rate regardless of demand

Applied Aspects

Acute pancreatitis — premature intrapancreatic activation of trypsinogen → autodigestion; the whole point of the zymogen system is to prevent this
Enzyme induction by drugs — rifampicin, phenytoin, carbamazepine and alcohol induce cytochrome P450 → failure of oral contraceptives and warfarin
Enzyme inhibition by drugs — cimetidine, erythromycin, ketoconazole inhibit P450 → toxicity of co-administered drugs
α1-antitrypsin deficiency — loss of a natural protease inhibitor → unopposed elastase → emphysema and liver disease
Phenobarbitone induces UDP-glucuronyl transferase — formerly used to treat neonatal jaundice by increasing bilirubin conjugation

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