1-Halo analogs of dihydroxyacetone 3-phosphate. The effects of the fluoro analog on cytosolic glycerol-3-phosphate dehydrogenase and triosephosphate isomerase

Joan B. Silverman, Paula S. Babiarz, Kishan P. Mahajan, John Buschek, Thomas P Fondy

Research output: Contribution to journalArticle

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Abstract

1-Fluoro-3-hydroxyacetone phosphate (fluoroacetol phosphate) has been prepared by oxidation of 1-fluoro-3-chloro-2-propanol to 1-fluoro-3-chloroacetone, phosphorylation with silver dibenzylphosphate, and the intermediate isolation of 1-fluoro-3-hydroxyacetone phosphate dibenzyl ester, followed by catalytic hydrogenation and preparation of the stable monosodium salt. The chloro analog as the pure, stable monosodium salt has been prepared by a similar route from 1,3-dichloroacetone. 1-Fluoro-3-hydroxyacetone-P is a substrate for cytosolic NAD +-linked glycerol-3-P dehydrogenase (EC 1.1.1.8) from rabbit skeletal muscle with an apparent K m of 50 mM under conditions in which dihydroxyacetone-P exhibits an apparent K m of 0.15 mM. Under these conditions the fluoro analog is 85% hydrated whereas dihydroxyacetone-P has been shown by others to be 44% hydrated. The turnover numbers are 49,000 molecules of NADH oxidized per minute per molecule of enzyme at 25° with the fluoro analog as substrate, and 60,000 with dihydroxyacetone-P as substrate. The product of the reduction of the fluoro analog has been identified as 1-fluorodeoxyglycerol-3-P. 1-Fluoro-3-hydroxyacetone-P is a comparatively weak irreversible inhibitor at 4° of rabbit muscle triosephosphate isomerase (EC 5.3.1.1) with a second-order rate constant of 2.6 M -1 sec -1. Inhibition by pyrazole in vivo of the alcohol dehydrogenase catalyzed oxidation of 1-fluorodeoxyglycerol-3-P indicates that in mice the reduction of 1-fluoro-3-hydroxyacetone-P to L-1-fluorodeoxyglycerol-3-P is not a significant metabolic route, or that an alternative route exists when the alcohol dehydrogenase dependent pathway is inhibited.

Original languageEnglish (US)
Pages (from-to)2252-2258
Number of pages7
JournalBiochemistry
Volume14
Issue number10
StatePublished - 1975

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Dihydroxyacetone
Dihydroxyacetone Phosphate
Triose-Phosphate Isomerase
Glycerolphosphate Dehydrogenase
Alcohol Dehydrogenase
NAD
Muscle
Substrates
Salts
Rabbits
Oxidation
Phosphorylation
Molecules
Hydrogenation
2-Propanol
Silver
Glycerol
Rate constants
Oxidoreductases
Esters

ASJC Scopus subject areas

  • Biochemistry

Cite this

1-Halo analogs of dihydroxyacetone 3-phosphate. The effects of the fluoro analog on cytosolic glycerol-3-phosphate dehydrogenase and triosephosphate isomerase. / Silverman, Joan B.; Babiarz, Paula S.; Mahajan, Kishan P.; Buschek, John; Fondy, Thomas P.

In: Biochemistry, Vol. 14, No. 10, 1975, p. 2252-2258.

Research output: Contribution to journalArticle

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abstract = "1-Fluoro-3-hydroxyacetone phosphate (fluoroacetol phosphate) has been prepared by oxidation of 1-fluoro-3-chloro-2-propanol to 1-fluoro-3-chloroacetone, phosphorylation with silver dibenzylphosphate, and the intermediate isolation of 1-fluoro-3-hydroxyacetone phosphate dibenzyl ester, followed by catalytic hydrogenation and preparation of the stable monosodium salt. The chloro analog as the pure, stable monosodium salt has been prepared by a similar route from 1,3-dichloroacetone. 1-Fluoro-3-hydroxyacetone-P is a substrate for cytosolic NAD +-linked glycerol-3-P dehydrogenase (EC 1.1.1.8) from rabbit skeletal muscle with an apparent K m of 50 mM under conditions in which dihydroxyacetone-P exhibits an apparent K m of 0.15 mM. Under these conditions the fluoro analog is 85{\%} hydrated whereas dihydroxyacetone-P has been shown by others to be 44{\%} hydrated. The turnover numbers are 49,000 molecules of NADH oxidized per minute per molecule of enzyme at 25° with the fluoro analog as substrate, and 60,000 with dihydroxyacetone-P as substrate. The product of the reduction of the fluoro analog has been identified as 1-fluorodeoxyglycerol-3-P. 1-Fluoro-3-hydroxyacetone-P is a comparatively weak irreversible inhibitor at 4° of rabbit muscle triosephosphate isomerase (EC 5.3.1.1) with a second-order rate constant of 2.6 M -1 sec -1. Inhibition by pyrazole in vivo of the alcohol dehydrogenase catalyzed oxidation of 1-fluorodeoxyglycerol-3-P indicates that in mice the reduction of 1-fluoro-3-hydroxyacetone-P to L-1-fluorodeoxyglycerol-3-P is not a significant metabolic route, or that an alternative route exists when the alcohol dehydrogenase dependent pathway is inhibited.",
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T1 - 1-Halo analogs of dihydroxyacetone 3-phosphate. The effects of the fluoro analog on cytosolic glycerol-3-phosphate dehydrogenase and triosephosphate isomerase

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N2 - 1-Fluoro-3-hydroxyacetone phosphate (fluoroacetol phosphate) has been prepared by oxidation of 1-fluoro-3-chloro-2-propanol to 1-fluoro-3-chloroacetone, phosphorylation with silver dibenzylphosphate, and the intermediate isolation of 1-fluoro-3-hydroxyacetone phosphate dibenzyl ester, followed by catalytic hydrogenation and preparation of the stable monosodium salt. The chloro analog as the pure, stable monosodium salt has been prepared by a similar route from 1,3-dichloroacetone. 1-Fluoro-3-hydroxyacetone-P is a substrate for cytosolic NAD +-linked glycerol-3-P dehydrogenase (EC 1.1.1.8) from rabbit skeletal muscle with an apparent K m of 50 mM under conditions in which dihydroxyacetone-P exhibits an apparent K m of 0.15 mM. Under these conditions the fluoro analog is 85% hydrated whereas dihydroxyacetone-P has been shown by others to be 44% hydrated. The turnover numbers are 49,000 molecules of NADH oxidized per minute per molecule of enzyme at 25° with the fluoro analog as substrate, and 60,000 with dihydroxyacetone-P as substrate. The product of the reduction of the fluoro analog has been identified as 1-fluorodeoxyglycerol-3-P. 1-Fluoro-3-hydroxyacetone-P is a comparatively weak irreversible inhibitor at 4° of rabbit muscle triosephosphate isomerase (EC 5.3.1.1) with a second-order rate constant of 2.6 M -1 sec -1. Inhibition by pyrazole in vivo of the alcohol dehydrogenase catalyzed oxidation of 1-fluorodeoxyglycerol-3-P indicates that in mice the reduction of 1-fluoro-3-hydroxyacetone-P to L-1-fluorodeoxyglycerol-3-P is not a significant metabolic route, or that an alternative route exists when the alcohol dehydrogenase dependent pathway is inhibited.

AB - 1-Fluoro-3-hydroxyacetone phosphate (fluoroacetol phosphate) has been prepared by oxidation of 1-fluoro-3-chloro-2-propanol to 1-fluoro-3-chloroacetone, phosphorylation with silver dibenzylphosphate, and the intermediate isolation of 1-fluoro-3-hydroxyacetone phosphate dibenzyl ester, followed by catalytic hydrogenation and preparation of the stable monosodium salt. The chloro analog as the pure, stable monosodium salt has been prepared by a similar route from 1,3-dichloroacetone. 1-Fluoro-3-hydroxyacetone-P is a substrate for cytosolic NAD +-linked glycerol-3-P dehydrogenase (EC 1.1.1.8) from rabbit skeletal muscle with an apparent K m of 50 mM under conditions in which dihydroxyacetone-P exhibits an apparent K m of 0.15 mM. Under these conditions the fluoro analog is 85% hydrated whereas dihydroxyacetone-P has been shown by others to be 44% hydrated. The turnover numbers are 49,000 molecules of NADH oxidized per minute per molecule of enzyme at 25° with the fluoro analog as substrate, and 60,000 with dihydroxyacetone-P as substrate. The product of the reduction of the fluoro analog has been identified as 1-fluorodeoxyglycerol-3-P. 1-Fluoro-3-hydroxyacetone-P is a comparatively weak irreversible inhibitor at 4° of rabbit muscle triosephosphate isomerase (EC 5.3.1.1) with a second-order rate constant of 2.6 M -1 sec -1. Inhibition by pyrazole in vivo of the alcohol dehydrogenase catalyzed oxidation of 1-fluorodeoxyglycerol-3-P indicates that in mice the reduction of 1-fluoro-3-hydroxyacetone-P to L-1-fluorodeoxyglycerol-3-P is not a significant metabolic route, or that an alternative route exists when the alcohol dehydrogenase dependent pathway is inhibited.

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