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Inhibitors of Pyruvate Carboxylase Tonya N Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 1-1-2010 Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki University of Wisconsin - Madison Martin St. Maurice Marquette University, [email protected] Paul V. Attwood University of Western Australia Published version. The Open Enzyme Inhibition Journal, Vol. 3 (2010): 8-26. DOI. © 2010 Bentham Open. Used with permission. This is an open access article licensed under the terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) 8 The Open Enzyme Inhibition Journal, 2010, 3, 8-26 Open Access Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki1, Martin St. Maurice2 and Paul V. Attwood3,* 1Department of Biochemistry, University of Wisconsin, Madison, WI 53726, USA 2Department of Biological Sciences, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA 3School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA6009, Australia Abstract: This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. Keywords: Pyruvate carboxylase, biotin-dependent enzyme, avidin, biotin, nucleotide inhibitors, acetyl coenzyme A, allosteric inhibitors, chlorothricin. INTRODUCTION also a corresponding decrease in GSIS. The decreased PC activity and expression observed in the islets of diabetic rats, Pyruvate carboxylase (PC, EC 6.4.1.1), a regulatory which are insulin resistant and show little GSIS [9, 10] metabolic enzyme responsible for replenishing the interme- further suggests that PC plays an important role in both GSIS diates of the TCA cycle and catalyzing the first committed and -cell adaptation to insulin resistance in fully function- step in gluconeogenesis, is found in a wide variety of ing pancreatic cells. While the mechanism by which PC organisms including bacteria, fungi, plants, invertebrates and activity regulates and enhances GSIS is not completely un- vertebrates [1]. Eukaryotic PC is generally located in the derstood, it has been proposed by MacDonald [11] and oth- mitochondria with the exception of yeast, where the two iso- ers [12] that the metabolic cycling of pyruvate through PC forms of PC (Pyc1 and Pyc2) are encoded by different genes, and the subsequent formation of anaplerotic by-products, and fungal PC, both of which are localized in the cytoplasm including NADPH, aids in modulating GSIS in pancreatic [2]. islets. Abnormalities in PC activity and regulation have been Abnormally, high hepatic PC activity was initially associated with the occurrence of Type II diabetes [3] result- observed in diabetic rats [5, 9, 10]. Deterioration of the GSIS ing in impaired-glucose tolerance and insulin insensitivity pathway, due in part to chronic exposure to fatty acids, [4]. In pre-diabetic patients, pancreatic islets compensate for decreases the ability of the -cells to secrete insulin, and the escalating insulin-resistance by increasing glucose- stimulated insulin secretion (GSIS) [3, 5]. Studies performed can lead to the development of Type II diabetes [5, 13]. by Jensen and co-workers [6] proposed that GSIS activity Metabolic flux through hepatic PC is normally attenuated was tightly correlated with the PC-catalyzed anaplerotic flux by the insulin-signaling pathway [14], but is increased in through the TCA cycle and subsequent cycling of pyruvate Type II diabetics resulting in raised hepatic glucose produc- through the malate-pyruvate shuttle. Recently, the use of tion [3, 13]. The metabolic abnormalities in the regulation small interfering RNA (si-RNA) to partially suppress PC and activities of PC associated with Type II diabetes make activity in INS-1 83/13-derived cell lines by Hasan et al. [7] PC an attractive molecular target for the development of demonstrated that decreases in GSIS were directly propor- new therapeutic agents for the treatment of this progressive tional to decreases in PC activity. Furthermore, Liu et al. [8] disease. previously observed a 2-fold increase in in vivo PC -cell Fan and co-workers [15] have recently established a con- activity and GSIS in obese, non-diabetic, insulin-resistant nection between PC activity and the “mitochondria dysfunc- Zucker fatty rats as compared to non-insulin resistant Zucker tion” observed in malignant lung cancer [16]. 13C isotopomer lean rats. Inhibition of PC by the addition of phenylacetate analysis by NMR revealed direct evidence for increased resulted in not only a marked decrease in PC activity, but glycolytic activity in malignant tumor cells and further demonstrated that both PC expression and activity, in vivo, were activated in human lung cancer. Previously, a nearly *Address correspondence to this author at the School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, 100-fold increase in PC’s anaplerotic activity was observed Crawley, WA6009, Australia; Tel: +61 8 6488 3329; Fax: +61 8 6488 1148; in in vitro studies of breast cancer cells [17] and PC’s E-mail: [email protected] gluconeogenic activity was found to be elevated in hepatic 1874-9402/10 2010 Bentham Open Inhibitors of Pyruvate Carboxylase The Open Enzyme Inhibition Journal, 2010, Volume 3 9 tumors in rats [18], demonstrating that increased PC activity PCs is highly regulated by acetyl CoA, PC from some bacte- correlates with the uncontroled proliferation of tumor cells. rial and fungi sources have no acetyl CoA dependence [1]. Therefore, the selective inhibition of PC activities in tumor Similar to other biotin-dependent carboxylases, including cells may prove to be a viable, alternative target for newly acetyl CoA carboxylase, propionyl CoA carboxylase and emerging antiproliferative cancer treatments. methyl malonyl CoA carboxylase, PC catalyses the carboxy- The connection between abnormal PC activity, Type II lation of pyruvate in two distinct steps which occur at diabetes and cancer substantiates the importance of under- discrete active sites (Fig. 1A). Biotin, which is covalently standing the structure, mechanism and inhibition of this attached to the -NH2 of a strictly conserved lysine residue regulatory enzyme. The native structure of PC from most located at the C-terminal end of the BCCP, is carboxylated at sources is an ()4 tetramer, where the biotin carboxylase the N-1 position in the BC domain via the ATP-dependent (BC), carboxyl transferase (CT), biotin-carboxyl carrier pro- activation of bicarbonate and formation of a putative tein (BCCP) and allosteric, or tetramerization, domains are carboxyphosphate intermediate [22]. Acting as a mobile contained on a single polypeptide chain, although it has been carboxyl carrier, carboxybiotin is then translocated from the shown that some bacterial PCs have an ()4 structure with BC domain to a neighbouring CT domain where it is decar- the BC domain forming the subunit and the CT and BCCP boxylated (Fig. 1B). Prior to carboxylation, the transfer of a domains forming the subunit. Recently, the structures of proton from pyruvate to biotin, facilitated by a strictly con- PC holoenzymes from Rhizobium etli [19] and Staphylococ- served Thr residue, is proposed to aid in the formation the cus aureus [20, 21] have been determined. These structures, nucleophilic enol-pyruvate [23]. The carboxyl group is then along with site directed mutagenic studies [19], revealed that transferred to the nucleophilic substrate, forming oxaloace- the covalently attached biotin moves between the BC domain tate (Fig. 1B). of one subunit to the CT domain of a neighbouring subunit A wealth of structural and kinetic data has been reported located on an opposing polypeptide chain [19] thus giving for PC, contributing greatly to a detailed description of the rise to a distinctive form of intersubunit catalysis. Further- PC mechanism. The aim of this review is to focus specifi- more, acetyl CoA, an allosteric activator of PC from several cally on the inhibition of PC as it relates to both the devel- sources, binds in the allosteric domain [19] and appears to opment of the current mechanistic model of PC activity and facilitate the interdomain movement of the BCCP and cova- the physiological regulation of the enzyme activity (Table 1). lently attached biotin. While the activity of most vertebrate (A) Biotin carboxylase domain H H H H H N N N N N O - O O O O N N N N H H N H O C - O O C O H B O O- O O C OH O O- O- OH O O - - Mg2+ O P O - O- Mg2+ O P O O P O 2+ - Mg - - 2+ O 2+ - O P O Mg O- Mg O- O P O ADP O ADP O carboxy ADP ADP ADP phosphate Carboxybiotin interdomain movement (B) Carboxyl transferase domain NH NH NH NH - O HN O HN O HN O HN N N N N C O HO H O H O O O Thr Thr Thr - HO O H O H C H Thr O C O C CH - CH3 2 CH2 O CH2 O O- O- O- O O O O O O O O +2 +2 Zn+2 Zn+2 Zn Zn Fig. (1). Overall PC-catalysed reaction. A) Biotin carboxylation occurring in the
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