tailieunhanh - Báo cáo khoa học: The crystal structure of human a-amino-b-carboxymuconatee-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis

The enzyme a-amino-b-carboxymuconate-e-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and deter-mines the final fate of the amino acid, . transformation into PA, com-plete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. | The crystal structure of human a-amino-p-carboxymuconate-e-semialdehyde decarboxylase in complex with 1 3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis Silvia Garavaglia1 Silvia Perozzi1 Luca Galeazzi2 Nadia Raffaelli2 and Menico Rizzi1 1 DiSCAFF Dipartimento di Scienze Chimiche Alimentari Farmaceutiche e Farmacologiche University of Piemonte Orientale A. Avogadro Novara Italy 2 Department of Molecular Pathology and Innovative Therapies Section of Biochemistry Universita Politecnica delle Marche Ancona Italy Keywords cerebral malaria kynurenine pathway metal-dependent amidohydrolase NAD biosynthesis neurological disorders Correspondence M. Rizzi DiSCAFF University of Piemonte Orientale Via Bovio 6 28100 Novara Italy Fax 39 0321 375821 Tel 39 0321 375712 E-mail rizzi@ Database The atomic coordinates and structure factors of hACMSD have been deposited with the Protein Data Bank http with accession codes 2wm1 and r2wm1 respectively Received 1 July 2009 revised 8 September 2009 accepted 10 September 2009 doi The enzyme a-amino-p-carboxymuconate-e-semialdehyde decarboxylase ACMSD is a zinc-dependent amidohydrolase that participates in picolinic acid PA quinolinic acid QA and NAD homeostasis. Indeed the enzyme stands at a branch point of the tryptophan to NAD pathway and determines the final fate of the amino acid . transformation into PA complete oxidation through the citric acid cycle or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions mainly affecting the central nervous system. As their relative concentrations must be tightly controlled modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders including cerebral malaria. Here we report the A resolution crystal structure of human ACMSD in complex with the glycolytic intermediate