Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Silva, Margarida F. B.; Ruiter, J. P. N.; IJlst, Lodewijk; Allers, Paul; Brink, H.J. ten; Jakobs, Cornelis; Durán, Marinus; Almeida, Isabel Tavares de; Wanders, Ronald J. A.

doi:10.1006/abio.2000.4947

Cited by 42 publications

(45 citation statements)

References 25 publications

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“…A synthetic procedure using a mixed anhydride intermediate was chosen to prepare ␤-phenylalanoyl-CoA as a cosubstrate for functional screening of the set of recombinant transferases. In brief, ␤-phenylalanine was converted to N-t-Boc-␤-phenylalanine by standard methods (22) and then esterified with CoA by using established procedures (16)(17)(18) that involve formation of a mixed anhydride between an alkyl͞aryl carboxylic acid and ethyl formic acid. Facile removal of the t-Boc group by trifluoroacetic acid treatment, followed by rapid purification of the product by reversed-phase chromatography, afforded pure ␤-phenylalanoyl-CoA in high yield.…”

Section: Resultsmentioning

confidence: 99%

“…The general procedure for the synthesis of the amino acid-CoA thioesters was adapted from literature methods (16)(17)(18) that used a mixed anhydride intermediate to facilitate transesterification with CoA. In each case, lyophilized Nprotected (and O-protected when necessary) amino acid-CoA ester intermediates were typically dissolved in 5-7 ml of buffer (15 mM potassium phosphate, pH 6.9) and purified by chromatography on a C 18 Sep-Pak cartridge (500 mg of C 18 silica gel, Waters) that was first washed with methanol (10 ml), then with water (10 ml), and finally with phosphate buffer (10 ml).…”

Section: Methodsmentioning

confidence: 99%

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Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

Walker

Fujisaki

Long

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

100

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

Walker

Fujisaki

Long

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

100

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“…Previous work from Li et al (1991), Ito et al (1990), and our group (Silva et al, 2001b(Silva et al, , 2002(Silva et al, , 2004) has led to the partial resolution of the mitochondrial ␤-oxidation pathway of VPA. We concluded that the enzymes involved in the oxidation of straight-chain fatty acids, including very long-, long-, medium-, and short-chain acyl-CoA dehydrogenases, are not involved in the first dehydrogenation reaction of VPA.…”

Section: Introductionmentioning

confidence: 83%

“…VP-CoA (Silva et al, 2001b), VP-DephCoA (Silva et al, 2004), and 2-methylbutyryl-CoA (Rasmussen et al, 1990) were synthesized as described previously.…”

Section: Downloaded Frommentioning

confidence: 99%

“…We also demonstrate that IVD is able to produce ⌬ 2(E) -valproyl-CoA (⌬ 2(E) -VPCoA), although with a much lower catalytic efficiency. Furthermore, we have investigated the potential inhibitory effect of VPA and some of its mitochondrial metabolites, especially in the form of the corresponding acyl-CoA intermediates VP-CoA and valproyl-dephosphoCoA (VP-DephCoA) (Silva et al, 2001b(Silva et al, , 2004, on the activity of IVD, IBD, and SBCAD. The implications of these findings with respect to the treatment of patients by VPA are discussed.…”

Section: Introductionmentioning

confidence: 99%

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Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

Luis¹,

Ruiter²,

IJlst³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Many biological systems including the oxidative catabolic pathway for branched-chain amino acids (BCAAs) are affected in vivo by valproate therapy. In this study, we investigated the potential effect of valproic acid (VPA) and some of its metabolites on the metabolism of BCAAs. In vitro studies were performed using isovalerylCoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase (IBD), and short branched-chain acyl-CoA dehydrogenase (SBCAD), enzymes involved in the degradation pathway of leucine, valine, and isoleucine. The enzymatic activities of the three purified human enzymes were measured using optimized high-performance liquid chromatography procedures, and the respective kinetic parameters were determined in the absence and presence of VPA and the corresponding CoA and dephosphoCoA conjugates. Valproyl-CoA and valproyl-dephosphoCoA inhibited IVD activity significantly by a purely competitive mechanism with K i values of 74 ؎ 4 and 170 ؎ 12 M, respectively. IBD activity was not affected by any of the tested VPA esters. However, valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K i of 249 ؎ 29 M. In addition, valproyl-dephosphoCoA inhibited SBCAD activity via a distinct mechanism (K i ‫؍‬ 511 ؎ 96 M) that appeared to be of the mixed type. Furthermore, we show that both SBCAD and IVD are active, using valproyl-CoA as a substrate. The catalytic efficiency of SBCAD turned out to be much higher than that of IVD, demonstrating that SBCAD is the most probable candidate for the first dehydrogenation step of VPA ␤-oxidation. Our data explain some of the effects of valproate on the branched-chain amino acid metabolism and shed new light on the biotransformation pathway of valproate.

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Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

Subramanian

Frank

Tangallapally

et al. 2022

J of Inher Metab Disea

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Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671.

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Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Cited by 42 publications

References 25 publications

Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

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