Coenzyme A metabolism

Robishaw, Janet D.; Neely, James R.

doi:10.1152/ajpendo.1985.248.1.e1

Cited by 109 publications

(154 citation statements)

References 63 publications

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“…7). This finding is contrary to several reports of PanK inhibition by unesterified CoA in mammalian tissue extracts (17,32,33,(33)(34)(35)(36)40), although inhibition by CoA is always less potent than regulation by acetyl-CoA. CoA stimulation may be masked in cell extracts if the stimulation of mPanK1␤ by unesterified CoA is a unique property of this isoform.…”

Section: Discussioncontrasting

confidence: 96%

“…Enhanced expression of mPanK1␤ protein reduced the intracellular pantothenate level below detection limits, in contrast to control cells where pantothenate comprised a significant pool. Both observations are consistent with the idea that PanK activity governs the flux through the CoA biosynthetic pathway (17)(18)(19). Whereas the supply of extracellular pantothenate (2 M) was sufficient to maintain a detectable pool of intracellular pantothenate in the control cultures, pantothenate may have been limiting to CoA production in the pmPanK1␤-transfected cultures (Figs.…”

Section: Discussionsupporting

confidence: 92%

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Pantothenate Kinase Regulation of the Intracellular Concentration of Coenzyme A

Rock¹,

Calder²,

Karim³

et al. 2000

Journal of Biological Chemistry

185

174

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Pantothenate kinase (PanK) is the key regulatory enzyme in the CoA biosynthetic pathway in bacteria and is thought to play a similar role in mammalian cells. We examined this hypothesis by identifying and characterizing two murine cDNAs that encoded PanK. The two cDNAs were predicted to arise from alternate splicing of the same gene to yield different mRNAs that encode two isoforms (mPanK1␣ and mPanK1␤) with distinct amino termini. The predicted protein sequence of mPanK1 was not related to bacterial PanK but exhibited significant similarity to Aspergillus nidulans PanK. mPanK1␣ was most highly expressed in heart and kidney, whereas mPanK1␤ mRNA was detected primarily in liver and kidney. Pantothenate was the most abundant pathway component (42.8%) in normal cells providing clear evidence that pantothenate phosphorylation was a ratecontrolling step in CoA biosynthesis. Enhanced mPanK1␤ expression eliminated the intracellular pantothenate pool and triggered a 13-fold increase in intracellular CoA content. mPanK1␤ activity in vitro was stimulated by CoA and strongly inhibited by acetyl-CoA illustrating that differential modulation of mPanK1␤ activity by pathway end products also contributed to the management of CoA levels. These data support the concept that the expression and/or activity of PanK is a determining factor in the physiological regulation of the intracellular CoA concentration.Pantothenate kinase (PanK) 1 (ATP:D-pantothenate 4Ј-phosphotransferase, EC 2.7.1.33) catalyzes the first committed step in the universal biosynthetic pathway leading to CoA (for review see Ref. 1). Phosphopantothenate is rapidly metabolized to CoA, which participates as an acyl group carrier in the tricarboxylic acid cycle, fatty acid metabolism, and numerous other reactions of intermediary metabolism (2). The 4Ј-phosphopantetheine portion of CoA is an essential prosthetic group in a number of enzyme systems including the acyl carrier protein components, bacterial and eukaryotic fatty acid synthases (3), citrate lyase (4), ferrichrome synthetase from Apsergillus quadricinctus (5), and malonate decarboxylase of Malonomonas rubra (6).PanK is the rate-controlling enzyme in CoA biosynthesis in Escherichia coli (1). E. coli is capable of de novo pantothenate biosynthesis, and additionally a sodium-dependent permease actively transports exogenous pantothenate into the cell (7-9). Metabolic labeling experiments established that the utilization, rather than the supply of pantothenate, controls the level of CoA (10). E. coli mutants with temperature-sensitive PanK activity are also temperature-sensitive for CoA biosynthesis and growth (11). The PanK gene of E. coli (coaA) was cloned by functional complementation of this mutant and was identical to a previously sequenced allele called rts (12)(13)(14). E. coli PanK (bPanK) is a homodimer of 36-kDa subunits that exhibit highly positive cooperative ATP binding and mediate sequential ordered catalysis with ATP as the leading substrate (15). CoA and its thioesters inhibit bPanK activity by co...

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 92%

Pantothenate Kinase Regulation of the Intracellular Concentration of Coenzyme A

Rock¹,

Calder²,

Karim³

et al. 2000

Journal of Biological Chemistry

185

174

View full text Add to dashboard Cite

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“…18,20 Indeed, Pank1-knockout Many of the previously identified p53 metabolic targets play significant roles in modulating the effect of p53-dependent apoptosis or growth arrest. GAMT, while not sufficient to trigger cell death, is required to induce the full apoptotic response after p53 activation.…”

Section: Discussionmentioning

confidence: 99%

“…The PanK family of proteins catalyze the first and rate-limiting step of CoA synthesis (phosphorylation of precursor pantothenate), and thus control the cellular content of CoA. 18 There are two PanK isoforms encoded by the PANK1 gene, PanK1α and PanK1β, and two other isoforms (PanK2 and PanK3) encoded by two other distinct genes. PanK1 is most highly expressed in the liver and corresponds to the liver possessing the highest concentration of CoA among tissues.…”

Section: Introductionmentioning

confidence: 99%

p53-dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene

Wang

Jiang

et al. 2013

Cell Cycle

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“…Coenzyme A is biosynthesized in five invariant steps from pantothenate (vitamin B 5 ), cysteine and ATP (Robishaw & Neely, 1985). The fourth step in the biosynthetic pathway is the adenylylation of 4 0 -phosphopantetheine using ATP to form dephospho-coenzyme A and pyrophosphate (Martin & Drueckhammer, 1993).…”

Section: Introductionmentioning

confidence: 99%

Structures of phosphopantetheine adenylyltransferase fromBurkholderia pseudomallei

et al. 2011

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PDB References: PPAT, 3pxu; 3k9w.Phosphopantetheine adenylyltransferase (PPAT) catalyzes the fourth of five steps in the coenzyme A biosynthetic pathway, reversibly transferring an adenylyl group from ATP onto 4 0 -phosphopantetheine to yield dephosphocoenzyme A and pyrophosphate. Burkholderia pseudomallei is a soil-and waterborne pathogenic bacterium and the etiologic agent of melioidosis, a potentially fatal systemic disease present in southeast Asia. Two crystal structures are presented of the PPAT from B. pseudomallei with the expectation that, because of the importance of the enzyme in coenzyme A biosynthesis, they will aid in the search for defenses against this pathogen. A crystal grown in ammonium sulfate yielded a 2.1 Å resolution structure that contained dephospho-coenzyme A with partial occupancy. The overall structure and ligand-binding interactions are quite similar to other bacterial PPAT crystal structures. A crystal grown at low pH in the presence of coenzyme A yielded a 1.6 Å resolution structure in the same crystal form. However, the experimental electron density was not reflective of fully ordered coenzyme A, but rather was only reflective of an ordered 4 0 -diphosphopantetheine moiety.

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Coenzyme A metabolism

Cited by 109 publications

References 63 publications

Pantothenate Kinase Regulation of the Intracellular Concentration of Coenzyme A

Pantothenate Kinase Regulation of the Intracellular Concentration of Coenzyme A

p53-dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene

Structures of phosphopantetheine adenylyltransferase fromBurkholderia pseudomallei

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