Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates

Kim S. Lau; Arthur J L Cooper; David T. Chuang

doi:10.1016/0167-4838(90)90249-F

Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates

Kim S. Lau, Arthur J L Cooper, David T. Chuang

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9 Scopus citations

Abstract

A novel class of inhibitors for the branched-chain 2-oxo acid dehydrogenase (BCOAD) complex has been synthesized and studied. The sodium salts of arylidenepyruvates: e.g., furfurylidenepyruvate (compound I), 4-(3-thienyl)-2-oxo-3-butenoate (compound II), cinnamalpyruvate (compound III) and 4-(2-thienyl)-2-oxo-3-butenoate (compound IV) inhibit the overall and kinase reactions of the BCOAD complex from bovine liver. Inhibitions of the overall reaction occur at the decarboxylase (E1) step as determined by a spectrophotometric assay with 2,6-dichlorophenolindophenol as an electron acceptor. Inhibition of the E1 reaction by compound I (K_i = 0.5 μM) is competitive, whereas inhibitions by compounds II (K_i = 150 μM) and III (K_i=500μM) are non-competitive with respect to the substrate 2-oxoisovalerate. The K_m value for 2-oxoisovalerate is 6.7 μM as measured by the E1 assay. Inhibition of the E1 step by compounds I, II and III are reversible at low inhibitor concentrations based on the Michaelis-Menten kinetics observed. By comparison, compound I does not significantly inhibit pyruvate and 2-oxoglutarate dehydrogenase complexes. The arylidenepyruvates (compounds I, II and IV) inhibit the BCOAD kinase reaction in a manner similar to the substrate 2-oxo acids. The inhibition of the kinase reaction by compound I is non-competitive with respect to ATP, with an apparent K_i value of 4.5 mM. The results suggest that arylidenepyruvates may be useful probes for elucidating the reaction mechanisms of the BCOAD complex and its kinase.

Original language	English (US)
Pages (from-to)	360-366
Number of pages	7
Journal	Biochimica et Biophysica Acta (BBA)/Protein Structure and Molecular
Volume	1038
Issue number	3
DOIs	https://doi.org/10.1016/0167-4838(90)90249-F
State	Published - May 8 1990

Keywords

(Bovine liver)
Arylidenepyruvate
Branched chain 2-oxo acid dehydrogenase complex
Inhibitor
Kinase

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology

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10.1016/0167-4838(90)90249-F

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title = "Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates",

abstract = "A novel class of inhibitors for the branched-chain 2-oxo acid dehydrogenase (BCOAD) complex has been synthesized and studied. The sodium salts of arylidenepyruvates: e.g., furfurylidenepyruvate (compound I), 4-(3-thienyl)-2-oxo-3-butenoate (compound II), cinnamalpyruvate (compound III) and 4-(2-thienyl)-2-oxo-3-butenoate (compound IV) inhibit the overall and kinase reactions of the BCOAD complex from bovine liver. Inhibitions of the overall reaction occur at the decarboxylase (E1) step as determined by a spectrophotometric assay with 2,6-dichlorophenolindophenol as an electron acceptor. Inhibition of the E1 reaction by compound I (Ki = 0.5 μM) is competitive, whereas inhibitions by compounds II (Ki = 150 μM) and III (Ki=500μM) are non-competitive with respect to the substrate 2-oxoisovalerate. The Km value for 2-oxoisovalerate is 6.7 μM as measured by the E1 assay. Inhibition of the E1 step by compounds I, II and III are reversible at low inhibitor concentrations based on the Michaelis-Menten kinetics observed. By comparison, compound I does not significantly inhibit pyruvate and 2-oxoglutarate dehydrogenase complexes. The arylidenepyruvates (compounds I, II and IV) inhibit the BCOAD kinase reaction in a manner similar to the substrate 2-oxo acids. The inhibition of the kinase reaction by compound I is non-competitive with respect to ATP, with an apparent Ki value of 4.5 mM. The results suggest that arylidenepyruvates may be useful probes for elucidating the reaction mechanisms of the BCOAD complex and its kinase.",

keywords = "(Bovine liver), Arylidenepyruvate, Branched chain 2-oxo acid dehydrogenase complex, Inhibitor, Kinase",

author = "Lau, {Kim S.} and Cooper, {Arthur J L} and Chuang, {David T.}",

note = "Funding Information: This work was supported by Grants DK37373, DK26758 and DK16739 from the National Institutes of Health, and by Grant 1-1149 from the March of Dimes Birth Defects Foundation. The mass spectrographic studies reported herein were aided by Grant RR-862 from The Division of Research Facilities and Re-",

year = "1990",

month = may,

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doi = "10.1016/0167-4838(90)90249-F",

language = "English (US)",

volume = "1038",

pages = "360--366",

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T1 - Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates

AU - Lau, Kim S.

AU - Cooper, Arthur J L

AU - Chuang, David T.

N1 - Funding Information: This work was supported by Grants DK37373, DK26758 and DK16739 from the National Institutes of Health, and by Grant 1-1149 from the March of Dimes Birth Defects Foundation. The mass spectrographic studies reported herein were aided by Grant RR-862 from The Division of Research Facilities and Re-

PY - 1990/5/8

Y1 - 1990/5/8

N2 - A novel class of inhibitors for the branched-chain 2-oxo acid dehydrogenase (BCOAD) complex has been synthesized and studied. The sodium salts of arylidenepyruvates: e.g., furfurylidenepyruvate (compound I), 4-(3-thienyl)-2-oxo-3-butenoate (compound II), cinnamalpyruvate (compound III) and 4-(2-thienyl)-2-oxo-3-butenoate (compound IV) inhibit the overall and kinase reactions of the BCOAD complex from bovine liver. Inhibitions of the overall reaction occur at the decarboxylase (E1) step as determined by a spectrophotometric assay with 2,6-dichlorophenolindophenol as an electron acceptor. Inhibition of the E1 reaction by compound I (Ki = 0.5 μM) is competitive, whereas inhibitions by compounds II (Ki = 150 μM) and III (Ki=500μM) are non-competitive with respect to the substrate 2-oxoisovalerate. The Km value for 2-oxoisovalerate is 6.7 μM as measured by the E1 assay. Inhibition of the E1 step by compounds I, II and III are reversible at low inhibitor concentrations based on the Michaelis-Menten kinetics observed. By comparison, compound I does not significantly inhibit pyruvate and 2-oxoglutarate dehydrogenase complexes. The arylidenepyruvates (compounds I, II and IV) inhibit the BCOAD kinase reaction in a manner similar to the substrate 2-oxo acids. The inhibition of the kinase reaction by compound I is non-competitive with respect to ATP, with an apparent Ki value of 4.5 mM. The results suggest that arylidenepyruvates may be useful probes for elucidating the reaction mechanisms of the BCOAD complex and its kinase.

AB - A novel class of inhibitors for the branched-chain 2-oxo acid dehydrogenase (BCOAD) complex has been synthesized and studied. The sodium salts of arylidenepyruvates: e.g., furfurylidenepyruvate (compound I), 4-(3-thienyl)-2-oxo-3-butenoate (compound II), cinnamalpyruvate (compound III) and 4-(2-thienyl)-2-oxo-3-butenoate (compound IV) inhibit the overall and kinase reactions of the BCOAD complex from bovine liver. Inhibitions of the overall reaction occur at the decarboxylase (E1) step as determined by a spectrophotometric assay with 2,6-dichlorophenolindophenol as an electron acceptor. Inhibition of the E1 reaction by compound I (Ki = 0.5 μM) is competitive, whereas inhibitions by compounds II (Ki = 150 μM) and III (Ki=500μM) are non-competitive with respect to the substrate 2-oxoisovalerate. The Km value for 2-oxoisovalerate is 6.7 μM as measured by the E1 assay. Inhibition of the E1 step by compounds I, II and III are reversible at low inhibitor concentrations based on the Michaelis-Menten kinetics observed. By comparison, compound I does not significantly inhibit pyruvate and 2-oxoglutarate dehydrogenase complexes. The arylidenepyruvates (compounds I, II and IV) inhibit the BCOAD kinase reaction in a manner similar to the substrate 2-oxo acids. The inhibition of the kinase reaction by compound I is non-competitive with respect to ATP, with an apparent Ki value of 4.5 mM. The results suggest that arylidenepyruvates may be useful probes for elucidating the reaction mechanisms of the BCOAD complex and its kinase.

KW - (Bovine liver)

KW - Arylidenepyruvate

KW - Branched chain 2-oxo acid dehydrogenase complex

KW - Inhibitor

KW - Kinase

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Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates

Abstract

Keywords

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