Biochemical communication between filament‐forming enzymes

Abstract

A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C.

Crosstalk between co‐assembling filamentous enzymes

“…The hypothesis presented by Stephen Bearne in this issue [1] suggests an intriguing new function for the recently observed and unexpected co-localization of two seemingly unrelated enzymes (CTPS and P5CS).…”

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The hypothesis presented by Stephen Bearne in this issue [1] suggests an intriguing new function for the recently observed and unexpected co-localization of two seemingly unrelated enzymes (CTPS and P5CS).CTPS or CTP synthetase is important in pyrimidine biosynthesis and catalyzes the conversion of UTP, glutamine, and ATP to CTP, glutamate, ADP, and phosphate. P5CS or Δ 1 -pyrroline-5-carboxylate synthase is important in proline biosynthesis and catalyzes the conversion of glutamate to glutamate-γ-semialdehyde (GSA), which is in an unfavorable equilibrium with its cyclic form Δ 1 -pyrroline-5-carboxylate (P5C).

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