Mammalian ACSF3 Protein Is a Malonyl-CoA Synthetase That Supplies the Chain Extender Units for Mitochondrial Fatty Acid Synthesis

Witkowski, Andrzej; Thweatt, Jennifer; Smith, Stuart

doi:10.1074/jbc.m111.291591

Cited by 59 publications

(58 citation statements)

References 39 publications

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“…Mitochondrial malonyl-CoA derived from ACSF3 has been implicated as a significant source of carbon for type II fatty acid synthesis in the mitochondrial matrix (Guan and Nikolau, 2016; Witkowski et al, 2011). The octanoyl-ACP (acyl-carrier protein) produced by de novo fatty acid synthesis in the mitochondrial matrix is a substrate for the synthesis of lipoic acid, an essential cofactor for α-ketoacid dehydrogenase complexes (reviewed in (Hiltunen et al, 2010; Hiltunen et al, 2009)).…”

Section: Resultsmentioning

confidence: 99%

“…How malonyl-CoA, which is membrane-impermeable, can be generated in the mitochondrial matrix has been a longstanding mystery. This has been at least partly resolved by the discovery of a eukaryotic mitochondrial malonyl-CoA synthetase, ACSF3 (Chen et al, 2011; Witkowski et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

“…Like other acyl-CoA synthetases, ACSF3 ligates Coenzyme A to its co-substrate, malonate, in an ATP-dependent manner (Figure 1A). Human ACSF3 localizes to the mitochondrial matrix to produce malonyl-CoA from malonate within that organelle (Witkowski et al, 2011). Mitochondrial malonate is an endogenous metabolite that is a classic competitive inhibitor of succinate dehydrogenase, a component of the tricarboxylic acid (TCA) cycle and Complex II of the electron transport chain (Quastel and Wooldridge, 1928).…”

Section: Introductionmentioning

confidence: 99%

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The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

Bowman

Rodriguez

Alpergin

et al. 2017

Cell Chemical Biology

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Summary Malonyl-CoA is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, that produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing. ACSF3 KO cells exhibited elevated malonate and impaired mitochondrial metabolism. Unbiased and targeted metabolomics analysis of KO and control cells in the presence or absence of exogenous malonate revealed metabolic changes dependent on either malonate or malonyl-CoA. While ACSF3 was required for the metabolism and therefore detoxification of malonate, ACSF3-derived malonyl-CoA was specifically required for lysine malonylation of mitochondrial proteins. Together, these data describe an essential role for ACSF3 in dictating the metabolic fate of mitochondrial malonate and malonyl-CoA in mammalian metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

Bowman

Rodriguez

Alpergin

et al. 2017

Cell Chemical Biology

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“…These CoAs can possibly be synthesized by their corresponding short-chain acyl salts, malonate, succinate, and glutarate, catalyzed by acyl-CoA synthetases, such as succinyl-CoA synthetase and malonyl-CoA synthetase (33,34). Additionally, these CoAs can be generated and consumed in the TCA cycle, as well as by metabolism of amino acids and lipids.…”

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confidence: 99%

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Hirschey

Zhao

2015

Molecular & Cellular Proteomics

365

311

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Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. Molecular & Cellular

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“…1) and has been isolated from a variety of soil bacteria and from mammalian mitochondria (27,33,34,63). The beststudied member of this group is MatB from the nitrogen-fixing legume symbiont Rhizobium leguminosarum bv.…”

mentioning

confidence: 99%

Structure-Guided Expansion of the Substrate Range of Methylmalonyl Coenzyme A Synthetase (MatB) of Rhodopseudomonas palustris

Crosby

Rank

Rayment

et al. 2012

Appl Environ Microbiol

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ABSTRACTMalonyl coenzyme A (malonyl-CoA) and methylmalonyl-CoA are two of the most commonly used extender units for polyketide biosynthesis and are utilized to synthesize a vast array of pharmaceutically relevant products with antibacterial, antiparasitic, anticholesterol, anticancer, antifungal, and immunosuppressive properties. Heterologous hosts used for polyketide production such asEscherichia colioften do not produce significant amounts of methylmalonyl-CoA, however, requiring the introduction of other pathways for the generation of this important building block. Recently, the bacterial malonyl-CoA synthetase class of enzymes has been utilized to generate malonyl-CoA and methylmalonyl-CoA directly from malonate and methylmalonate. We demonstrate that in the purple photosynthetic bacteriumRhodopseudomonas palustris, MatB (RpMatB) acts as a methylmalonyl-CoA synthetase and is required for growth on methylmalonate. We report theapo(1.7-Å resolution) and ATP-bound (2.0-Å resolution) structure and kinetic analysis ofRpMatB, which shows similar activities for both malonate and methylmalonate, making it an ideal enzyme for heterologous polyketide biosynthesis. Additionally, rational, structure-based mutagenesis of the active site ofRpMatB led to substantially higher activity with ethylmalonate and butylmalonate, demonstrating that this enzyme is a prime target for expanded substrate specificity.

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Mammalian ACSF3 Protein Is a Malonyl-CoA Synthetase That Supplies the Chain Extender Units for Mitochondrial Fatty Acid Synthesis

Cited by 59 publications

References 39 publications

The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Structure-Guided Expansion of the Substrate Range of Methylmalonyl Coenzyme A Synthetase (MatB) of Rhodopseudomonas palustris

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