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ATP Citrate Lyase – Biology and Implication in Human Pathology

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ATP Citrate Lyase – Biology and Implication in Human Pathology Revista Român ă de Medicin ă de Laborator Vol. 12, Nr. 3, Septembrie 2008 17 ATP citrate lyase – biology and implication in human pathology ATP citrat liaza – biologie şi implicare în patologia uman ă Liviu S. Enache * Institut Fédératif de Recherche 128 ‘BioSciences Gerland – Lyon Sud’, INSERM, U851, Lyon, France Emergency Clinical Hospital, Medical Analysis Laboratory, Tîrgu Mure ş, Romania Abstract ATP citrate lyase (ACLY) is a cytoplasmic enzyme that catalyzes the cleavage of citrate into oxaloac- etate and acetyl-CoA. This reaction provides most of the acetyl-CoA required for the biosynthesis of fatty acids and cholesterol. Since its discovery half a century ago, many of the mechanisms involved in the regulation of ACLY activity have remained unclear. Various attempts to biochemically characterize the enzyme gave highly heterogeneous results. The development of expression systems for the recombinant human protein offered a pow- erful tool for research on this enzyme. Although the reaction catalyzed by ACLY is not rate limiting in either lipo- genesis or cholesterologenesis, its „strategic” metabolic position makes ACLY an appealing target for hypolipi- demic intervention. ACLY inhibition experiments showing hypolipidemic and hypocholoesterolemic effects in an- imal models, together with data suggesting the role of the enzyme in cancer biology, cell growth and differentia- tion, brought it in the attention of scientific community. This paper makes a review of ACLY biology and its po- tential implication in human pathology. Keywords: ATP citrate lyase, lipogenesis, enzyme inhibitors, hipolipidemic agents Rezumat ATP citrat liaza (ACLY) este o enzim ă situat ă în citoplasm ă, care catalizeaz ă scindarea citratului în oxaloacetat şi acetil-coenzima A. Aceast ă reac Ńie ofer ă majoritatea necesarului de acetil-coenzim ă A pentru bio- sinteza acizilor gra şi şi a colesterolului. Începând cu descoperirea sa în urm ă cu o jum ătate de secol, mai multe mecanisme implicate în reglarea activit ăŃ ii ACLY r ămân inc ă neclare. Încerc ările de a caracteriza enzima din punct de vedere biochimic au dat rezultate foarte variabile. Dezvoltarea sistemelor de expresie a proteinei uma- ne recombinante au oferit un instrument puternic pentru studierea acestei enzime. De şi reac Ńia catalizat ă de ACLY nu este limitant ă de vitez ă nici pentru lipogenez ă, nici pentru colesterologenez ă, pozi Ńia ei metabolic ă strategic ă face din ACLY o Ńint ă atr ăgătoare pentru interven Ńia hipolipemiant ă. Experimente de inhibare a ACLY care au demonstrat efecte hipolipemiante şi hipocolesterolemiante în modelele animale şi date sugerând rolul enzimei în biologia cancerului, în cre şterea şi diferen Ńierea celular ă, au adus-o în aten Ńia comunit ăŃ ii ştiin Ńifice. Aceast ă lucrare constituie o prezentare general ă asupra biologiei ACLY şi a implic ării sale în patologia uman ă. Cuvinte-cheie: ATP citrat liaza, lipogenez ă, inhibitori enzimatici, agen Ńi hipolipemian Ńi. *Address for correspondence: Emergency Clinical Hospital, Str. Gh. Marinescu, Nr. 50, Tîrgu Mure ş, Romania Tel. 0040724882779, E-mail: [email protected] 18 Revista Român ă de Medicin ă de Laborator Vol. 12, Nr. 3, Septembrie 2008 Fatty acids synthesis Glucose Cholesterologenesis Malonyl-CoA Gluconeogenesis Glucose-6-P ACETYL-CoA CARBOXYLASE Fructose-6-P Oxaloacetate Acetyl-CoA Acetate NADH+H + phosphorylation Pyruvate MDH CoA Insulin ATP CITRATE NAD + ATP Glucagon LYASE + Allosteric Malate Citrate activation Phosphorylated sugars P T + PYRUVATE Malate DEHYDROGENASE Pyruvate Acetyl-CoA Citrate Oxaloacetate Citric acid cycle Malate MITOCHONDRION Figure 1. Involvement of ATP citrate lyase in several metabolic pathways. MDH = malate dehydrogenase, P = pyruvate transporter, T = tricarboxylate transporter ATP citrate lyase (ACLY) i is a cyto- catabolism of the carbon skeletons of amino plasmic enzyme that catalyses the cleavage of acids. The mitochondrial inner membrane is im- citrate into oxaloacetate and acetyl-CoA, the permeable to acetyl-CoA, so an indirect shuttle latter being the major building block for both transfers acetyl group equivalents across the in- cholesterologenesis and lipogenesis ( Figure 1 ). ner membrane. Intramitochondrial acetyl-CoA Acetyl-CoA provided by ACLY is also used in first reacts with oxaloacetate to form citrate in the biosynthesis of acetylcholine. Oxaloacetate the citric acid cycle, reaction catalyzed by cit- enters the gluconeogenic pathway through rate synthase. Citrate then passes through the phosphoenolpyruvate carboxykinase. inner membrane on the citrate transporter. In In nonruminants, nearly all the acetyl- the cytosol, citrate cleavage by ACLY regener- CoA used in fatty acid synthesis is formed in ates acetyl-CoA in an ATP-dependent reac- mitochondria from pyruvate oxidation and from tion 24 . Although the reaction catalyzed by i EC 2.3.3.8 (created in 1965 as EC 4.1.3.8, modified ACLY is not rate limiting in either lipo- or in 1986, transferred in 2002 to EC 2.3.3.8). System- cholesterologenesis, its „strategic” metabolic atic name: acetyl-CoA:oxaloacetate C-acetyltrans- position upstream of acetyl-CoA carboxylase ferase [(pro-S)-carboxymethyl-forming, ADP-phos- and hydroxymethyl glutaryl coenzyme A reduc- phorylating]. Synonyms: ATP-citrate synthase, tase attracted researchers to select this enzyme ATP-citrate (pro-S-)-lyase, Citrate cleavage enzyme Revista Român ă de Medicin ă de Laborator Vol. 12, Nr. 3, Septembrie 2008 19 as a target for hypolipidemic intervention. Re- CoA synthetase is not reported to involve the sults of ACLY inhibition experiments showing production of a covalent succinyl-enzyme as hypolipidemic and hypocholoesterolemic ef- part of the mechanism 36 . The structural and fects in animal models, together with data sug- functional similarity between the two enzymes gesting the role of the enzyme in cancer biolo- led to further investigations which showed that gy, cell growth and differentiation, brought it the mechanism of the reaction for ACLY pro- again in the attention of scientific community. ceeds as far as the production of an enzyme - This paper makes a review of ACLY citryl-phosphate complex. However, the next biology and its potential implication in human stage of the reaction is therefore most likely to pathology. be the direct attack of CoA on the citrate phos- phate. Therefore, only one covalent enzyme- Reaction mechanism bound intermediate occurs in the ATP-citrate- lyase-catalysed reaction 36 . The novel proposed mechanism was also confirmed by the failure in The reaction catalysed by ACLY is the attempts to inhibit enzyme activity using shown in Equation 1 . compounds that interacted with the active site A five-step reaction mechanism was thiol nucleophile 10 . initially proposed, where enzyme was first phosphorylated by ATP and the phosphate was transferred to citrate to form a non-covalent cit- Structure ryl phosphate within the active site. The citrate was then transferred to a thiol nucleophile en- Since the early work of Srere and his zyme active site to form a covalent citryl-en- collaborators 30 who purified ACLY from chick- zyme complex which was then attacked by CoA en liver, the methods of production and purifi- to generate citryl-CoA within the active site. Fi- cation of the active enzyme have evolved, per- nally, the enzyme catalysed the retro-Claisen mitting detailed analysis of its structure and cleavage of citryl-CoA to produce acetyl-CoA function. Cloning and expression of human and oxaloacetate 36 . ACLY have been achieved 8 and large quantities The primary sequence of rat liver of active enzyme can now be obtained in bac- ACLY has been obtained from a cDNA clone ulovirus expression system 19 . and its amino acid sequence was showed to The enzyme is a tetramer (molecular have a high similarity with the alpha chain of mass of 440 KDa as determined by sedimenta- succinyl-CoA synthetase of Escherichia coli 7. tion equilibrium) of four apparently identical Both enzymes catalyse similar reactions. The subunits 29 . Each subunit has a sequence of 1101 first reaction step for both of them is autophos- amino acids and a calculated mass of 120,8 phorylation of the enzyme by ATP, followed by KDa 34 . Human ACLY amino acid sequence is phosphorylation of the substrate (citrate and 96,3% identical to rat ACLY and the inclusion succinate, respectively) by the phosphoenzyme of conservative replacements increases the de- formed. CoA reacts with citrate/succinate phos- gree of similarity to 98% 8. phate to form citryl-/succinyl- CoA. ACLY has Studies on this enzyme showed that the one additional step in that citryl-CoA is cleaved isolated protein was a phosphoprotein contain- into acetyl-CoA and oxaloacetate before re- ing usually two phosphate groups per lease. However, the mechanism of succinyl- tetramer 18 . ++ Citrate + ATP + CoA ←Mg →acetyl − CoA + oxaloaceta te + ADP + Pi Equation 1. Reaction catalyzed by ATP citrate lyase 20 Revista Român ă de Medicin ă de Laborator Vol. 12, Nr. 3, Septembrie 2008 Table 1. Features of ATP citrate lyase chain 34 Feature Key Position Length Description Regions Nucleotide binding 701-721 21 ATP (by similarity) Nucleotide binding 752 - 778 27 ATP (by similarity) Region 779 - 789 11 CoA-binding (potential) Sites Active site 760 1 Tele-phosphohystidine intermediate (by similarity) Metal binding 718 1 Magnesium (by similarity) Amino acid modifications Modified residue 131 1 Phosphotyrosine Modified residue 455 1 Phosphoserine Modified residue 481 1 Phosphoserine Modified residue 682 1 Phosphotyrosine Natural variations Natural variant 175 1 Glu →Asp A summary of sequence annotations in ACLY mRNA. In young individuals, ACLY (features) on the chain of an ACLY subunit as mRNA is increased in brain, as lipogenesis is described in UniProtKB (Protein Knowledge- also an important pathway in the developing base) 34 are presented in Table 1 . brain, particularly with respect to myelination 7. A diurnal variation in ACLY mRNA in rat liver Enzyme distribution in tissues and was demonstrated. However, no diurnal varia- tion in activity of the enzyme was observed 9. cellular localization The activity of ACLY is lower in hu- man tissues compared to rat tissues.
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