Biochemistry: flux, enzymes and the fed-fast switch
Biochemistry questions test whether you can follow carbon and nitrogen through the fed and fasted states and predict what happens when a single enzyme fails. Metabolism, vitamins and cofactors, and the molecular biology of replication, transcription and translation are the three reliable clusters.
Core rules
- Glycolysis is regulated at phosphofructokinase-1, activated by AMP and fructose-2,6-bisphosphate, inhibited by ATP and citrate. Glucokinase sets the hepatic threshold, hexokinase sets the muscle rate.
- Pyruvate dehydrogenase irreversibly commits pyruvate to acetyl-CoA and needs thiamine pyrophosphate; deficiency raises lactate after a carbohydrate load.
- Gluconeogenesis cannot run in reverse of glycolysis; it uses pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase.
- Vitamins: thiamine deficiency gives beriberi and Wernicke encephalopathy; niacin deficiency gives pellagra (dermatitis, diarrhoea, dementia); B12 deficiency gives macrocytic anaemia with neurological signs, folate does not.
Worked example
A 6-month-old with hepatomegaly has fasting glucose 2.1 mmol/L, lactate 6 mmol/L, uric acid raised, triglycerides raised, and no response to glucagon. The combination of fasting hypoglycaemia with lactic acidosis and hyperuricaemia points to glucose-6-phosphatase deficiency (von Gierke disease). Without that enzyme, glucose-6-phosphate cannot leave the liver as glucose, so it diverts into glycolysis (lactate), the pentose phosphate pathway and purine degradation (urate), and into fat. Glycogen accumulates, hence the hepatomegaly. Glucagon fails because the liver can mobilise glycogen but cannot release the glucose.
Traps that cost marks
- Adenosine triphosphate yield and the number of substrate-level phosphorylations are easily confused with the NADH yield.
- Carnitine shuttle transports long-chain fatty acids; short and medium chains enter without it.
- Folate supplementation can mask B12 deficiency anaemia while neuropathy progresses.
- Rate-limiting enzyme questions often offer glucokinase when the answer is phosphofructokinase-1.