Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase

Richard D. Gandour; William J. Colucci; Terry C. Stelly; Paul S. Brady; Linda J Brady

doi:10.1016/0003-9861(88)90058-6

Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase

Richard D. Gandour, William J. Colucci, Terry C. Stelly, Paul S. Brady, Linda J Brady

Food Science and Nutrition

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Abstract

We have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorpholinium bromide (hemipalmitoylcarnitinium, HPC), which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (K_i(app) = 5.1 ± 0.7 μM) and palmitoyl-CoA (K_i(app = 21.5 ± 4.9 μM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (K_i(app = 1.6 ± 0.6 μM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, K_i(app)'s 14.2 ± 2.1 μm relative to (R)-carnitine and 8.7 ± 2.6 μm relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (K_i(app = 18.6 ± 4.5 μM) and with palmitoyl CoA (K_i(app = 10.4 ± 2.5 μM). Choline is not an effective CPT inhibitor. We have shown [R. D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.

Original language	English (US)
Pages (from-to)	515-520
Number of pages	6
Journal	Archives of Biochemistry and Biophysics
Volume	267
Issue number	2
DOIs	https://doi.org/10.1016/0003-9861(88)90058-6
State	Published - Dec 1988

Bibliographical note

Funding Information:
r The enzymological research was supported by the American Diabetes Association. ’ To whom correspondence should be addressed. ’ Abbreviations used: CAT, carnitine acetyltransferase; CPT, carnitine palmitoyltransferase; EGTA, ethylene glycol bis(p-aminoethyl ether) N,N’-tetraacetic acid, HAC, hemiacetylcarnitinium; HPC, hemi-

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Copyright 2014 Elsevier B.V., All rights reserved.

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@article{61ddc6e08e8e4ba79d232a87a744b5ac,

title = "Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase",

abstract = "We have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorpholinium bromide (hemipalmitoylcarnitinium, HPC), which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (Ki(app) = 5.1 ± 0.7 μM) and palmitoyl-CoA (Ki(app = 21.5 ± 4.9 μM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (Ki(app = 1.6 ± 0.6 μM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, Ki(app)'s 14.2 ± 2.1 μm relative to (R)-carnitine and 8.7 ± 2.6 μm relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (Ki(app = 18.6 ± 4.5 μM) and with palmitoyl CoA (Ki(app = 10.4 ± 2.5 μM). Choline is not an effective CPT inhibitor. We have shown [R. D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.",

author = "Gandour, {Richard D.} and Colucci, {William J.} and Stelly, {Terry C.} and Brady, {Paul S.} and Brady, {Linda J}",

note = "Funding Information: r The enzymological research was supported by the American Diabetes Association. {\textquoteright} To whom correspondence should be addressed. {\textquoteright} Abbreviations used: CAT, carnitine acetyltransferase; CPT, carnitine palmitoyltransferase; EGTA, ethylene glycol bis(p-aminoethyl ether) N,N{\textquoteright}-tetraacetic acid, HAC, hemiacetylcarnitinium; HPC, hemi- Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

year = "1988",

month = dec,

doi = "10.1016/0003-9861(88)90058-6",

language = "English (US)",

volume = "267",

pages = "515--520",

journal = "Archives of Biochemistry and Biophysics",

issn = "0003-9861",

publisher = "Academic Press Inc.",

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T1 - Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase

AU - Gandour, Richard D.

AU - Colucci, William J.

AU - Stelly, Terry C.

AU - Brady, Paul S.

AU - Brady, Linda J

N1 - Funding Information: r The enzymological research was supported by the American Diabetes Association. ’ To whom correspondence should be addressed. ’ Abbreviations used: CAT, carnitine acetyltransferase; CPT, carnitine palmitoyltransferase; EGTA, ethylene glycol bis(p-aminoethyl ether) N,N’-tetraacetic acid, HAC, hemiacetylcarnitinium; HPC, hemi- Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 1988/12

Y1 - 1988/12

N2 - We have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorpholinium bromide (hemipalmitoylcarnitinium, HPC), which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (Ki(app) = 5.1 ± 0.7 μM) and palmitoyl-CoA (Ki(app = 21.5 ± 4.9 μM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (Ki(app = 1.6 ± 0.6 μM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, Ki(app)'s 14.2 ± 2.1 μm relative to (R)-carnitine and 8.7 ± 2.6 μm relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (Ki(app = 18.6 ± 4.5 μM) and with palmitoyl CoA (Ki(app = 10.4 ± 2.5 μM). Choline is not an effective CPT inhibitor. We have shown [R. D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.

AB - We have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorpholinium bromide (hemipalmitoylcarnitinium, HPC), which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (Ki(app) = 5.1 ± 0.7 μM) and palmitoyl-CoA (Ki(app = 21.5 ± 4.9 μM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (Ki(app = 1.6 ± 0.6 μM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, Ki(app)'s 14.2 ± 2.1 μm relative to (R)-carnitine and 8.7 ± 2.6 μm relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (Ki(app = 18.6 ± 4.5 μM) and with palmitoyl CoA (Ki(app = 10.4 ± 2.5 μM). Choline is not an effective CPT inhibitor. We have shown [R. D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.

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Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase

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