Question

Ornithine, an intermediate of the urea cycle, and proline, found in proteins, are both synthesized from glutamate. How does this occur?

Short answer

Question: Explain how ornithine and proline are synthesized from glutamate. Answer: Ornithine and proline are synthesized from glutamate through a common first step, where glutamate is converted to delta-1-pyrroline-5-carboxylate (P5C) by the enzymes glutamate 5-kinase and glutamate-5-semialdehyde dehydrogenase. Ornithine is then formed from P5C via two different pathways, either through the enzyme ornithine delta-aminotransferase (OAT) in the liver and kidneys or by the enzyme delta-1-pyrroline-5-carboxylate reductase in other tissues. Proline, on the other hand, is formed through a direct one-step reaction, where P5C is reduced by the enzyme delta-1-pyrroline-5-carboxylate reductase using NADPH as a cofactor.

Step-by-step solution

Converting glutamate to delta-1-pyrroline-5-carboxylate (P5C)

The first step in the synthesis of both ornithine and proline is the conversion of glutamate to delta-1-pyrroline-5-carboxylate (P5C). This is catalyzed by the enzyme glutamate 5-kinase, which transfers a phosphate group from ATP to the C5 position of glutamate, forming an intermediate called gamma-glutamyl phosphate. The enzyme glutamate-5-semialdehyde dehydrogenase then facilitates the reduction of gamma-glutamyl phosphate to produce the final product P5C.

Formation of ornithine from P5C

P5C is then converted to ornithine via two different pathways. In the liver and kidneys (the main organs where the urea cycle occurs), the enzyme ornithine delta-aminotransferase (OAT) transfers the delta-amino group from P5C to 2-oxoglutarate, yielding ornithine and a molecule of glutamate (which can be further metabolized or returned to the starting point). Alternatively, in other tissues, P5C spontaneously hydrolyzes to form glutamate gamma-semialdehyde, which is then converted to ornithine by the enzyme delta-1-pyrroline-5-carboxylate reductase.

Formation of proline from P5C

The conversion of P5C to proline is a simple one-step reaction. This is facilitated by the enzyme delta-1-pyrroline-5-carboxylate reductase. Here, P5C is reduced by the enzyme using NADPH as a cofactor to form proline. In summary, the synthesis of both ornithine and proline from glutamate undergoes a common first step, the conversion of glutamate to P5C. Then, P5C is converted to ornithine via different pathways depending on the tissue where it occurs, while the formation of proline from P5C is a direct one-step reaction.