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Mechanistic Insights into Metabolon Formation and Substrate Channeling in Coenzyme Q Biosynthesis

ABSTRACT: Metabolons - transient assemblies of sequential metabolic enzymes - facilitate the reactions of multi-step metabolic pathways. They represent crucial metabolic fineries, yet, how they mechanistically bolster metabolic flux remains enigmatic. Here, we investigate the molecular determinants of metabolon formation and substrate channeling using coarse-grained molecular dynamics simulations and biophysical approaches to coenzyme Q biosynthesis. The COQ metabolon is fastenedsecured by predominantly weak protein-protein interactions and wherein the COQ6-COQ3 enzyme pair is a critical structural hub for metabolon genesis. Selectively disrupting protein-protein associations demonstrates that protein-proximity is imperative for substrate channeling. Randomly shuffling the interaction network nodes reveals that the specific spatial arrangement of consecutive enzymes has minimal effects on product yield. Rather than specific catalytic activities or fine architectural features, proximity between enzymes in complete clusters is pivotal for metabolic flux. We conclude that the COQ metabolon is evolutionarily optimized to generate complete enzyme clusters without strict requirements for specific spatial arrangements. These findings provide mechanistic insights into how metabolic enzymes are spatially organized to achieve enhance efficient multi-step biosynthesis.

INSTRUMENT(S):

ORGANISM(S): Synthetic Construct

SUBMITTER: Tereza Kadavá

LAB HEAD: Albert J.R. Heck

PROVIDER: PXD062263 | Pride | 2026-06-08

REPOSITORIES: Pride

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			Action	DRS
	20230711_EX2_UM7_kadav001_SA_EXT00_GF_COQ_DMTMM_1.raw	Raw
	20230711_EX2_UM7_kadav001_SA_EXT00_GF_COQ_DMTMM_2.raw	Raw
	20230711_EX2_UM7_kadav001_SA_EXT00_GF_COQ_DMTMM_3.raw	Raw
	20230711_EX2_UM7_kadav001_SA_EXT00_GF_COQ_DSS_1.raw	Raw
	20230711_EX2_UM7_kadav001_SA_EXT00_GF_COQ_DSS_2.raw	Raw

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Mechanistic Insights into Metabolon Formation and Substrate Channeling in Coenzyme Q Biosynthesis

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