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ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.

ABSTRACT: Hydroxylated fatty acids are important intermediates in lipid metabolism and signaling. Surprisingly, the metabolism of 4-hydroxy fatty acids remains largely unexplored. We found that both ACAD10 and ACAD11 unite two enzymatic activities to introduce these metabolites into mitochondrial and peroxisomal β-oxidation, respectively. First, they phosphorylate 4-hydroxyacyl-CoAs via a kinase domain, followed by an elimination of the phosphate to form enoyl-CoAs catalyzed by an acyl-CoA dehydrogenase (ACAD) domain. Studies in knockout cell lines revealed that ACAD10 preferentially metabolizes shorter chain 4-hydroxy fatty acids than ACAD11 (i.e. 6 carbons versus 10 carbons). Yet, recombinant proteins showed comparable activity on the corresponding 4-hydroxyacyl-CoAs. This suggests that the localization of ACAD10 and ACAD11 to mitochondria and peroxisomes, respectively, might influence their physiological substrate spectrum. Interestingly, we observed that ACAD10 is cleaved internally during its maturation generating a C-terminal part consisting of the ACAD domain, and an N-terminal part comprising the kinase domain and a haloacid dehalogenase (HAD) domain. HAD domains often exhibit phosphatase activity, but negligible activity was observed in the case of ACAD10. Yet, inactivation of a presumptive key residue in this domain significantly increased the kinase activity, suggesting that this domain might have acquired a regulatory function to prevent accumulation of the phospho-hydroxyacyl-CoA intermediate. Taken together, our work reveals that 4-hydroxy fatty acids enter mitochondrial and peroxisomal fatty acid β-oxidation via two enzymes with an overlapping substrate repertoire.

SUBMITTER: Paquay S

PROVIDER: S-EPMC11342911 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.

Paquay Stéphanie S Duraffourd Julia J Bury Marina M Heremans Isaac P IP Caligiore Francesco F Gerin Isabelle I Stroobant Vincent V Jacobs Jean J Pinon Aymeric A Graff Julie J Vertommen Didier D Van Schaftingen Emile E Dewulf Joseph P JP Bommer Guido T GT

Cellular and molecular life sciences : CMLS 20240822 1

Hydroxylated fatty acids are important intermediates in lipid metabolism and signaling. Surprisingly, the metabolism of 4-hydroxy fatty acids remains largely unexplored. We found that both ACAD10 and ACAD11 unite two enzymatic activities to introduce these metabolites into mitochondrial and peroxisomal β-oxidation, respectively. First, they phosphorylate 4-hydroxyacyl-CoAs via a kinase domain, followed by an elimination of the phosphate to form enoyl-CoAs catalyzed by an acyl-CoA dehydrogenase ( ...[more]

PMID: 39174697

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Project description:BackgroundGanoderic acids (GAs), recognized as significant triterpenoid bioactive components in Ganoderma lucidum, exhibit a broad spectrum of pharmacological activities, including immunomodulation, anti-cancer, and anti-aging properties. Despite their significant pharmacological potential, the low yield of GAs from natural sources has emerged as a critical bottleneck hindering their broader application in the pharmaceutical and health care industries. Previous studies have suggested that environmental perturbations can influence energy metabolism, potentially impacting the biosynthesis of bioactive compounds. However, the specific influence of environmental changes on energy metabolism and subsequent effects on GAs synthesis in G. lucidum remains an understudied area.ResultsWe demonstrated that intracellular ATP deficiency significantly influences GAs accumulation induced by alterations in energy metabolism. Intracellular ATP deficiency was consistently observed under all four known conditions that induce GAs accumulation: heat stress (HS), nitrogen limitation, treatment with 50 µM methyl jasmonate (MeJA), and treatment with 200 µM salicylic acid (SA). Consistent with these findings, silencing the ATP synthase beta subunit (ATPsyn-beta) or treating with oligomycin (Oli), an ATP synthase inhibitor, increased GAs accumulation and induced intracellular ATP deficiency in G. lucidum. Our results revealed an increase in the GAs biosynthetic pathway and increased levels of the GAs precursor acetyl-CoA in mycelia with intracellular ATP deficiency. Enhanced fatty acid β-oxidation was identified as the primary source of additional acetyl-CoA, indicating that this process, induced by intracellular ATP deficiency, is crucial for GAs accumulation.ConclusionsThis study demonstrated that changes in intracellular ATP content respond to environmental perturbations and impact the biosynthesis of GAs, holding substantial implications for production practices. Modulating ATP levels could increase GAs yields, cater to market demands, and reduce costs. The research also furnishes a scientific foundation for optimizing cultivation conditions, employing genetic engineering to refine biosynthetic pathways, and leveraging environmental control to boost production efficiency.

Dataset Information

ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.

Publications

ACAD10 and ACAD11 allow entry of 4-hydroxy fatty acids into β-oxidation.

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