Subcellular Localization and Regulation of Coenzyme A Synthase

Zhyvoloup, Alexander; Nemazanyy, Ivan; Panasyuk, Ganna; Valovka, Taras; Fenton, Tim R.; Rebholz, Heike; Wang, Mong‐Lien; Foxon, Richard; Lyzogubov, Valeriy V.; Usenko, Vasylij; Kyyamova, R. G.; Gorbenko, Olena; Matsuka, G. Kh.; Filonenko, Valeriy; Gout, Ivan

doi:10.1074/jbc.m307763200

Cited by 67 publications

(73 citation statements)

References 42 publications

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“…For example, tafazzin, a mitochondrial enzyme that catalyzes PC-cardiolipin transacylation in an acyl-CoA-independent manner, specifically prefers PC that contains linoleoyl residues as a substrate (25). CoA synthase, which is localized in the outer mitochondrial membrane, was reported to be activated by PC (26). Thus, the present study may facilitate research regarding the biological functions and importance of mitochondrial PC.…”

Section: Discussionmentioning

confidence: 91%

StarD7 Mediates the Intracellular Trafficking of Phosphatidylcholine to Mitochondria

Horibata

Sugimoto

2010

Journal of Biological Chemistry

121

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Steroidogenic acute regulatory protein-related lipid transfer (START) domains, found in 15 mammalian proteins termed StarD1-StarD15, are lipid-binding domains implicated in the intracellular lipid transport systems. In the present study, we analyzed the lipid ligand and function of StarD7. We found two variable forms of mammalian StarD7, termed StarD7-I and StarD7-II. Unlike StarD7-II, StarD7-I contained a mitochondrial-targeting sequence in its N terminus. Overexpressed StarD7-I tagged with V5/His in HEPA-1 cells was mainly observed in the mitochondria of cells prepared at low cellular density, but it was distributed in the cytoplasm of high density cells. StarD7-II was constantly distributed in the cytoplasm at any cellular density. Endogenous StarD7 in HEPA-1 cells and rat liver was also distributed in both the cytoplasm and the mitochondria. A protease K protection assay indicated that the mitochondrial StarD7 was associated with the outer mitochondrial membrane. The purified recombinant StarD7 specifically catalyzed the transfer of PC between lipid vesicles in vitro. Furthermore, the intracellular transport of fluorescent PC that was exogenously incorporated into the mitochondria was increased in cells that overexpressed StarD7-I. These results suggest that StarD7 facilitates the delivery of PC to mitochondria in non-vesicular system.

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Section: Discussionmentioning

confidence: 91%

StarD7 Mediates the Intracellular Trafficking of Phosphatidylcholine to Mitochondria

Horibata

Sugimoto

2010

Journal of Biological Chemistry

121

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“…Because in humans the biosynthesis of CoA takes place entirely outside the mitochondrial matrix (25,37,38), a primary function of SLC25A42 is to transport CoA into the mitochondria. In the mitochondrial matrix CoA has an essential role in major processes occurring in the organelles, such as the ␤-oxidation of fatty acids, the tricarboxylic acid cycle at the level of pyruvate and ␣-oxoglutarate dehydrogenases, the biosynthesis of heme at the level of ␦-aminolevulinate synthase, branchedchain amino acid catabolism, the urea cycle at the level of acetylglutamate synthase, and protein acetylation.…”

Section: Discussionmentioning

confidence: 99%

A Novel Member of Solute Carrier Family 25 (SLC25A42) Is a Transporter of Coenzyme A and Adenosine 3′,5′-Diphosphate in Human Mitochondria

Fiermonte

Paradies

Todisco

et al. 2009

Journal of Biological Chemistry

136

139

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Mitochondrial carriers are a family of proteins that transport metabolites, nucleotides, and cofactors across the inner mitochondrial membrane thereby connecting cytosolic and matrix functions. The essential cofactor coenzyme A (CoA) is synthesized outside the mitochondrial matrix and therefore must be transported into mitochondria where it is required for a number of fundamental processes. In this work we have functionally identified and characterized SLC25A42, a novel human member of the mitochondrial carrier family. The SLC25A42 gene (Haitina, T., Lindblom, J., Renström, T., and Fredriksson, R., 2006, Genomics 88, 779 -790) was overexpressed in Escherichia coli, purified, and reconstituted into phospholipid vesicles. Its transport properties, kinetic parameters, and targeting to mitochondria demonstrate that SLC25A42 protein is a mitochondrial transporter for CoA and adenosine 3,5-diphosphate. SLC25A42 catalyzed only a counter-exchange transport, exhibited a high transport affinity for CoA, dephospho-CoA, ADP, and adenosine 3,5-diphosphate, was saturable and inhibited by bongkrekic acid and other inhibitors of mitochondrial carriers to various degrees. The main physiological role of SLC25A42 is to import CoA into mitochondria in exchange for intramitochondrial (deoxy)adenine nucleotides and adenosine 3,5-diphosphate. This is the first time that a mitochondrial carrier for CoA and adenosine 3,5-diphosphate has been characterized biochemically.The mitochondrial carrier family, or the solute carrier family 25 (SLC25), 3 comprises a large group of proteins that transport a variety of substrates across the inner mitochondrial membrane and, in a few cases, across other membranes (1, 2). Common structural features of the mitochondrial carrier family members consist in a tripartite structure (three repeats of ϳ100 amino acids), the presence of two transmembrane ␣-helices separated by hydrophilic loops in each repeat, and the presence of a signature motif at the C terminus of the first helix in each repeat (Ref. 3 and references therein). The SLC25 family is by far the largest of the currently known 43 SLC families. The Saccharomyces cerevisiae genome contains 35 members, that of Arabidopsis thaliana 58, and the human genome at least 48 SLC25 members. Until now, nearly 30 members and isoforms of this family have been identified in humans. These include the uncoupling protein and the carriers for ADP/ATP, phosphate, 2-oxoglutarate/malate, citrate, carnitine/acylcarnitine, dicarboxylates, ornithine and other basic amino acids, oxodicarboxylates, deoxynucleotides and thiamine pyrophosphate, aspartate-glutamate, glutamate, S-adenosylmethionine, ATPMg/Pi, pyrimidine nucleotides, and adenine nucleotides in peroxisomes (see Ref. 1 for a review and Refs. 4 -8). The present investigation was undertaken to identify the function of SLC25A42, a novel member of the SLC25 family recently found in the human genome (9). SLC25A42 is 318 amino acids long and is highly expressed in virtually all tissues, in most at higher levels than ma...

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“…Interestingly, it has been shown that proteolytic cleavage of the human enzyme does not affect enzyme activity or the proposed tertiary structure [11]. Also, the N-terminal domain of the CoA synthase is found only in higher eukaryotes and has been shown to effect regulation of the CoaD and CoaE activities by phospholipids [12]. The amalgamation of the last two enzyme activities also hints at the existence of a currently-unknown, relatively recently evolved mechanism of regulation of the CoA biosynthetic pathway seen only in the higher eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

The Role of UPF0157 in the Folding of M. tuberculosis Dephosphocoenzyme A Kinase and the Regulation of the Latter by CTP

2009

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BackgroundTargeting the biosynthetic pathway of Coenzyme A (CoA) for drug development will compromise multiple cellular functions of the tubercular pathogen simultaneously. Structural divergence in the organization of the penultimate and final enzymes of CoA biosynthesis in the host and pathogen and the differences in their regulation mark out the final enzyme, dephosphocoenzyme A kinase (CoaE) as a potential drug target.Methodology/Principal FindingsWe report here a complete biochemical and biophysical characterization of the M. tuberculosis CoaE, an enzyme essential for the pathogen's survival, elucidating for the first time the interactions of a dephosphocoenzyme A kinase with its substrates, dephosphocoenzyme A and ATP; its product, CoA and an intrinsic yet novel inhibitor, CTP, which helps modulate the enzyme's kinetic capabilities providing interesting insights into the regulation of CoaE activity. We show that the mycobacterial enzyme is almost 21 times more catalytically proficient than its counterparts in other prokaryotes. ITC measurements illustrate that the enzyme follows an ordered mechanism of substrate addition with DCoA as the leading substrate and ATP following in tow. Kinetic and ITC experiments demonstrate that though CTP binds strongly to the enzyme, it is unable to participate in DCoA phosphorylation. We report that CTP actually inhibits the enzyme by decreasing its Vmax. Not surprisingly, a structural homology search for the modeled mycobacterial CoaE picks up cytidylmonophosphate kinases, deoxycytidine kinases, and cytidylate kinases as close homologs. Docking of DCoA and CTP to CoaE shows that both ligands bind at the same site, their interactions being stabilized by 26 and 28 hydrogen bonds respectively. We have also assigned a role for the universal Unknown Protein Family 0157 (UPF0157) domain in the mycobacterial CoaE in the proper folding of the full length enzyme.Conclusions/SignificanceIn view of the evidence presented, it is imperative to assign a greater role to the last enzyme of Coenzyme A biosynthesis in metabolite flow regulation through this critical biosynthetic pathway.

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Subcellular Localization and Regulation of Coenzyme A Synthase

Cited by 67 publications

References 42 publications

StarD7 Mediates the Intracellular Trafficking of Phosphatidylcholine to Mitochondria

StarD7 Mediates the Intracellular Trafficking of Phosphatidylcholine to Mitochondria

A Novel Member of Solute Carrier Family 25 (SLC25A42) Is a Transporter of Coenzyme A and Adenosine 3′,5′-Diphosphate in Human Mitochondria

The Role of UPF0157 in the Folding of M. tuberculosis Dephosphocoenzyme A Kinase and the Regulation of the Latter by CTP

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