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Regulation of Brain Pyruvate Dehydrogenase Multienzyme Complex

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Regulation of Brain Pyruvate Dehydrogenase Multienzyme Complex LE JOURNAL CANAD1EN DES SCIENCES NEUROLOGIQUES Regulation of Brain Pyruvate Dehydrogenase Multienzyme Complex T. T. NGO AND A. BARBEAU SUMMARY: A number of excellent and REACTION MECHANISM distinct enzymes: (1) pyruvate de- comprehensive reviews on various as­ The oxidative decarboxylation of carboxylaste (Ei) (also called pyru­ pects of pyruvate dehydrogenase mul­ pyruvate to form acetyl CoA and vate dehydrogenase); (2) dihyd- tienzyme complex have been written re­ CO2 at the expense of NAD is rolipoate transacetylase (E2); and (3) cently. The purpose of the present review dihydrolipoate dehydrogenase (E3). is to summarize briefly the reaction catalyzed by pyruvate dehyd­ mechanism and the regulation of this rogenase (PDH). In all organisms These enzymes catalyze the follow­ enzyme. Emphasis is put on the most studied, PDH is a multienzyme ing reactions (reactions 1 to 5) in a recent literature not covered by previous complex. In bacteria, it consists of 3 |sequential manner (Table I). reviews. Particular attention is also paid to the regulation of brain pyruvate de­ TABLE I hydrogenase multienzyme complex, since a number of patients with (1) CH -C-COOH + TPP-E:., > CH,-C-TPP-E + neuromuscular diseases, such as 1 C0„ Friedreich's ataxia, show a decreased 1 ' i \ 1 rate of pyruvate oxidation. OH 0 I II (2) CH3-C-TPP-E1 + (Lip S2)-E2 ^ (O^-C- S-Lip SH)-E2 + TPP-Ej^ RESUME: Un grand nombre de revues H completes sur les differents aspects du complexe multienzymatique de la pyru­ 0 0 vate deshydrogenase (PDH) ont ete 11 II recemment publies. Le but du present (3) (CH3-C-S-Lip SH)-E2 + CoA SH -} (Lip S2)-E2 + CH3-C-S-CoA travail sera de resumer certains points nouveaux concernant le mecanisme de la reaction el de la regulation de ce complexe enzymatique dont (4) Lip(SH)2-E2 + Ox.(FAD)-E3 (Lip S2)-E2 + red. (FAD)-E I'importance grandissante apparait dans I'etude de plusieurs maladies mus- culaires, dont Vataxie de Friedreich, qui toutes demontrent un ralentissement du taux d'oxydation du pyruvate. (5) Red. (FAD)-E + NAD -^ ox. (FAD)-E3 + NADH + H 0 O II II (6) Net reaction: CH -C-COOH + CoA SH + NAD CH3-C-S CoA + C02 + NADH + H Ei catalyzes reactions 1 and 2, E2 pyruvate dehydrogenase multien­ catalyzes reaction 3, E3 catalyzes zyme complex (Reed, 1960, 1974; reactions 4 and 5. E2 forms the core Hucho, 1975; Denton et al., 1975). of the complex, and Ei and E3 are attached to E2. The lipoyl group is The detailed chemical mechanism bound covalently to E2 via an amide of the pyruvate dehydrogenase linkage to the £ -amino group of a catalyzed reactions having been re­ lysyl residue in E2. This attachment viewed by Hucho (1975), only a very From the Department of Neurobiology, Clinical Research Institute of Montreal. provides a flexible arm, permitting brief survey will be given here. A the lipoyl group to rotate between schematic representation of the Reprint requests to: Dr. A. Barbeau, Clinical the catalytic centers of the three Research Institute of Montreal, 110 Pine Avenue reaction sequence of PDH is shown West, Montreal, Quebec, Canada H2W 1R7. associated enzymes which form the in Figure 1. Vol. 5, No. 2 MAY 1978-231 Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.219, on 01 Oct 2021 at 02:47:13, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100024598 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Ei catalyzes 2 reactions: 1) the decarboxylation of pyruvate which is initiated by its attachment to the 2-position of the thiazole ring of TPP. The loss of CO2 leads to hydroxyethyl-TPP. Magnesium ion is the co-factor of Ei; 2) the oxida­ tion of the hydroxyethyl group and transfer of the resulting acetyl group to lipoic acid of E2. Thus, in addition to the decarboxylating activity, Ei also possesses dehydrogenase and transferase activities. The reaction catalyzed by Ei is irreversible. The reaction sequence catalyzed by Ei can be summarized as: E2 catalyzes the transfer of the acetyl group of the dihydrolipoic acid to CoA SH. This reaction is reversible. E3 catalyzes the regeneration of active E2 making it possible for the Figure I—Sequence of the reaction catalyzed by pyruvate dehydrogenase multienzyme next catalytic cycle of the complex. m* i—^~R Regeneration of E2 occurs by the complex (PDH). TPP= thiamine pyrophosphate; s-s = oxidized lipoamide: s s = + transfer of two electrons from dihyd­ H H reduced lipoamide. CoA SH = coenzyme A; FAD=flavin adenine dinucleotide; rolipoic acid to NAD, a reaction in adeninNAD =e nicotinamiddinucleotidee ;adenin Ei = epyruvat dinucleotidee decarboxylase; NADH=; reduceE2 :dihydrolipoamidd form of nicotinamide transe- which two molecules of NAD, one acetylase; E3 = dihydrolipoamide dehydrogenase. molecule of FAD, and one disulfide group of the protein take part. Thus, functionally, E3 can be depicted as: 0 0 II II = CH3- C-C-OH ^l ^S +C02 PYRUVATE HO I 0 11 These chemical evidences of the REACTION A CH -C-S 3 reaction mechanism suggest that the ACETYL- over-all reaction catalyzed by pyru­ DIHYDROUPOATE vate dehydrogenase proceeds via a three-site "ping-pong" mechanism. Indeed, kinetic studies of Tsai, Burgett and Reed (1973) and of Ngo HS HS and Barbeau (J. Neurochem., in + HSCoA ^=±CH3-C-S-CoA + press, 1978) have provided evidence CH3-C-S HS that both bovine kidney and rat brain pyruvate dehydrogenase multien­ ACETYL- COENZYME A ACETYL CoA DIHYDRO- zyme complexes catalyze the reac­ DIHYDROUPOATE LIPOATE tion via a three-site "ping-pong" REACTION B mechanism. 232 - MAY 1978 Brain Pyruvate Dehydrogenase Regulation Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.219, on 01 Oct 2021 at 02:47:13, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100024598 LE JOURNAL CANADIEN DES SCIENCES NEUROLOG1QUES METABOLIC REGULATION 3. The acetyl CoA formed from ox­ ganisms differ from that of unicellu­ Pyruvate occupies a strategic pos­ idative decarboxylatation of lar organisms. The regulatory ition in the metabolism of both car­ pyruvate can be used for the start­ mechanisms that have evolved in bohydrates and lipids. Any enzyme ing material in the biosynthesis of bacteria are geared to achieve a max­ that catalyzes the metabolism of fatty acids, prostaglandins and imal rate of cell proliferation consis­ pyruvate is expected to be under steroidal hormones. tent with available nutritional sources. In contrast the individual strict metabolic regulation. The 4. Pyruvate supplies the carbon cell of a multicellular organism more complexity of the control skeleton for the de novo synthesis often divides slowly, and is variable mechanism arises from the position of alanine and cysteine. in degree of organisational com­ of pyruvate and pyruvate metaboliz­ plexity and in the type a specific ing enzyme in energy metabolism. The apparent activity of an en­ function it carries out. Such cells are This enzyme is at the crossroads of zyme can be regulated in many associated with both similar and dis­ several metabolic routes. Pyruvate ways. Enzyme activity can be mod­ similar cells into tissues and organs, is formed in glycolysis from glucose, ulated by extracellular agents such functioning as an integrated whole in as hormones or their second mes­ from lactate, and from amino acids the protection and propagation of sengers, i.e., cyclic nucleotides. In- such as alanine and cysteine. Con­ specialized cells. In bacteria, the re­ tracellularly, an enzyme activity can currently, it is the starting point of moval process can involve dilution be controlled by the following pro­ four important metabolic routes during phases of rapid growth. In cesses: (Figure 2): animal tissues, where little cellular 1. Pyruvate can be oxidatively de­ A) Coarse control mechanism division takes place, the process of graded to acetyl CoA and NADH A coarse control for enzyme activ­ protein degradation becomes in­ which finally, through the trica- ity means a long term regulation of creasingly significant as a means of boxylic acid cycle and via oxida­ enzyme activity by changing the removing unneeded metabolic tive phosphorylation, can gener­ concentration of enzyme. The en­ machinery, and as a means for con­ ate ATP. zyme level of cells can be increased trolling enzyme levels. 2. Pyruvate can also be carboxy- by induction (derepression) or de­ The interaction between the lated to form oxolacetate and thus creased by repression. The proces­ synthesis and degradation of specific can form the starting point of ses of enzyme induction and repres­ enzymes in controlling enzyme gluconeogenesis. sion in the cells of multicellular or- levels in animal tissues is reflected in a general comparison of differences GLUCOSE in the time course of enzyme induc­ tion in animal tissues and bacteria (Figure 3). In bacteria the total en­ * zyme activity increases, following the introduction of an inducer. Simi­ ->- PHOSPHOENOLPYRUVATE larly, in animal cells the level of enzyme can be increased by indue- \ ALANINE, CYSTEINE PYRUVATE LACTATE -IHDUCER ATP N^C02 >- /, t- 7 kN ACETYL CoA -*- FATTY ACIDS ^~ 1 \ ADP o ! N «* 1 Ul \ \ y // N N>l- // \ Uzl / / \ OXALACETATE *****' CITRATE / / \ / / v~ / / (- / / \y TIME Figure 5—Time courses of enzyme in­ Figure 2—Pathways of pyruvate metabolism showing the strategic position of pyru­ duction in bacteria (solid line) and vate at the crossroads of carbohydrate and lipid metabolisms. animal cells (broken line). Ngo and Barbeau MAY 1978 - 233 Downloaded from https://www.cambridge.org/core. IP address: 170.106.40.219, on 01 Oct 2021 at 02:47:13, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms.
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