The biosynthesis of coenzyme a in bacteria

Begley, Tadhg P.; Kinsland, Cynthia; Strauss, Erick

doi:10.1016/s0083-6729(01)61005-7

Cited by 204 publications

(163 citation statements)

References 45 publications

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“…PANK2 is a member of a family of eukaryotic genes encoding pantothenate kinases, which catalyze the phosphorylation of pantothenate (vitamin B5) to yield phosphopantothenate. This process is the first of five enzymatic steps in the biosynthesis of coenzyme A (CoA), a universal acyl carrier used by perhaps as many as 4% of all enzymes (Begley et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Kotzbauer¹,

Truax²,

Trojanowski³

et al. 2005

J. Neurosci.

136

126

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Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5Ј start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

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Section: Introductionmentioning

confidence: 99%

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Kotzbauer¹,

Truax²,

Trojanowski³

et al. 2005

J. Neurosci.

136

126

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“…Acetyl-CoA and succinyl-CoA are key intermediates in energy metabolism, taking part in the tricarboxylic acid cycle. It is therefore surprising that three of the CoA biosynthetic enzymes have only recently been identified in E. coli (2,3).Phosphopantothenoylcysteine decarboxylase (PPC-DC) catalyzes the decarboxylation of 4Ј-phosphopantothenoylcysteine (PPanCys) to form 4Ј-phosphopantetheine (Fig. 1).…”

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confidence: 99%

Phosphopantothenoylcysteine Synthetase from Escherichia coli

Strauss

Kinsland

et al. 2001

Journal of Biological Chemistry

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Phosphopantothenoylcysteine synthase catalyzes the formation of (R)-4-phospho-N-pantothenoylcysteine from 4-phosphopantothenate and L-cysteine: this enzyme, involved in the biosynthesis of coenzyme A (CoA), has not previously been identified. Recently it was shown that the NH 2 -terminal domain of the Dfp protein from bacteria catalyzes the next step in CoA biosynthesis, the decarboxylation of (R)-4-phospho-N-pantothenoylcysteine to form 4-phosphopantetheine (Kupke, T., Uebele, M., Schmid, D., Jung, G., Blaesse, M., and Steinbacher, S. (2000) J. Biol. Chem. 275, 31838 -31846). We have partially purified phosphopantothenoylcysteine decarboxylase from Escherichia coli and demonstrated that the protein encoded by the dfp gene, here renamed coaBC, also has phosphopantothenoylcysteine synthetase activity, using CTP rather than ATP as the activating nucleoside 5-triphosphate. This discovery completes the identification of all the enzymes involved in the biosynthesis of coenzyme A in bacteria.Coenzyme A (CoA) 1 fulfils a vital role in the normal metabolism of living organisms: it has been reported that ϳ4% of all enzymes utilize either CoA, its thioesters or 4Ј-phosphopantetheine (1). As an essential cofactor of fatty acid synthases, polyketide synthases, and nonribosomal peptide synthases, 4Ј-phosphopantetheine functions as an acyl group carrier, activating carboxylic acids for biological Claisen reactions and the formation of peptides and esters. Acetyl-CoA and succinyl-CoA are key intermediates in energy metabolism, taking part in the tricarboxylic acid cycle. It is therefore surprising that three of the CoA biosynthetic enzymes have only recently been identified in E. coli (2,3).Phosphopantothenoylcysteine decarboxylase (PPC-DC) catalyzes the decarboxylation of 4Ј-phosphopantothenoylcysteine (PPanCys) to form 4Ј-phosphopantetheine (Fig. 1). From a mechanistic perspective this reaction proves to be particularly interesting as it is unclear how the stabilization of the carbanion intermediate is achieved. To study this enzyme we have repeated, with major modifications, the published purification of PPC-DC from wild-type E. coli (4). Amino-terminal sequencing identified the dfp gene as coding for the protein having this activity. The flavin-containing Dfp protein was first identified from a temperature-sensitive mutant (dfp-707), believed to be involved in DNA and pantothenate metabolism (5, 6). However, the conditional lethality of the mutant was reported not to be a direct result of pantothenate auxotrophy, and its complete characterization was not achieved. While our work was in progress, Kupke et al. (7) also identified Dfp as having PPC-DC activity by sequence comparison with EpiD, a lantibiotic-synthesizing protein catalyzing the decarboxylation of peptidylcysteine intermediates.We now report that the protein encoded by dfp also catalyzes the formation of PPanCys from 4Ј-phosphopantothenate and L-cysteine using cytidine 5Ј-triphosphate (CTP) as the activating nucleoside 5Ј-triphosphate. The protein releases CM...

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“…Phosphorylation of dephospho-CoA is the last step in the biosynthetic pathway of CoA (Begley et al, 2001), a principal carrier for acetyl and acyl groups and important for the biosynthesis of fatty acids, polypeptide antibiotics and polyketides. Notably, some metabolites (e.g.…”

Section: Discussionmentioning

confidence: 99%

A gene encoding a potential adenosine 5′-phosphosulphate kinase is necessary for timely development of Myxococcus xanthus

Wang

Song

et al. 2016

Microbiology

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A Myxococcus xanthus gene, MXAN3487, was identified by transposon mutagenesis to be required for the expression of mcuABC, an operon coding for part of the chaperone-usher (CU) system in this bacterium. The MXAN3487 protein displays sequence and structural homology to adenosine 59-phosphosulphate (APS) kinase family members and contains putative motifs for ATP and APS binding. Although the MXAN3487 locus is not linked to other sulphate assimilation genes, its protein product may have APS kinase activity in vivo and the importance of the ATP-binding site for activity was demonstrated. Expression of MXAN3487 was not affected by sulphate availability, suggesting that MXAN3487 may not function in a reductive sulphate assimilation pathway. Deletion of MXAN3487 significantly delayed fruiting body formation and the production of McuA, a spore coat protein secreted by the M. xanthus Mcu CU system. Based on these observations and data from our previous studies, we propose that MXAN3487 may phosphorylate molecules structurally related to APS, generating metabolites necessary for M. xanthus development, and that MXAN3487 exerts a positive effect on the mcuABC operon whose expression is morphogenesis dependent.

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The biosynthesis of coenzyme a in bacteria

Cited by 204 publications

References 45 publications

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Phosphopantothenoylcysteine Synthetase from Escherichia coli

A gene encoding a potential adenosine 5′-phosphosulphate kinase is necessary for timely development of Myxococcus xanthus

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