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Roles of Vitamins B5, B8, B9, B12 and Molybdenum Cofactor at Cellular and Organismal Levels†

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Roles of Vitamins B5, B8, B9, B12 and Molybdenum Cofactor at Cellular and Organismal Levels† View Article Online / Journal Homepage / Table of Contents for this issue REVIEW www.rsc.org/npr | Natural Product Reports Roles of vitamins B5, B8, B9, B12 and molybdenum cofactor at cellular and organismal levels† Fabrice Rebeill´ e,*´ a Stephane´ Ravanel,a Andree´ Marquet,b Ralf R. Mendel,c Alison G. Smithd and Martin J. Warrene Received (in Cambridge, UK) 14th June 2007 First published as an Advance Article on the web 20th August 2007 DOI: 10.1039/b703104c Covering: 1984 to 2007 Many efforts have been made in recent decades to understand how coenzymes, including vitamins, are synthesised in organisms. In the present review, we describe the most recent findings about the biological roles of five coenzymes: folate (vitamin B9), pantothenate (vitamin B5), cobalamin (vitamin B12), biotin (vitamin B8) and molybdenum cofactor (Moco). In the first part, we will emphasise their biological functions, including the specific roles found in some organisms. In the second part we will present some nutritional aspects and potential strategies to enhance the cofactor contents in organisms of interest. 1 Introduction 1 Introduction 2 Biological functions 2.1 Main functions found in all organisms Cofactors are small molecules (at least compared to the size 2.1.1 Nucleic acid synthesis: the role of folate of a protein) that facilitate an enzyme to catalyze a reaction. 2.1.2 The methylation cycle: the roles of folate and These ‘chemical tools’ can be inorganic (metal ions or clusters) or cobalamin organic (coenzymes) and are generally involved in group transfer 2.1.3 Fatty acid biosynthesis and gluconeogenesis: the roles or redox reactions. They can act as co-substrates or be permanently of biotin and pantothenate associated with the structure of the enzyme (prosthetic groups). 2.1.4 Redox reactions: the role of Moco A large number of these coenzymes are derived from vitamins. 2.1.5 Other metabolic functions for folate, biotin and Vitamins, by definition, are dietary substances required for good cobalamin health and normal development of animals. Most of them are only 2.2 The main differences among eukaryotic organisms synthesised by microorganisms and plants. During the course of Published on 20 August 2007. Downloaded by Harvard University 19/11/2013 20:46:55. 2.2.1 Compartmentalisation animal evolution, the ability to biosynthesise these compounds 2.2.2 Specific needs in some eukaryotes has been lost and, instead, elaborate uptake mechanisms have 3 Nutritional aspects been developed. As many vitamins are only required in trace 3.1 Effects of deficiency on human health quantities, their biosynthesis is normally strictly controlled and the 3.2 Main dietary sources enzymes involved are produced in vanishingly small amounts. This 3.3 Strategies for enhancement is why it has been extremely difficult to elucidate their complete 4 Conclusion: compartmentalisation, a challenging biosynthetic pathways, and it still remains the case that many steps area within the biosynthesis of vitamins are poorly understood (see the 5 References review by Webb and Smith in this issue). Because they are essential in all organisms and are required in a number of biological processes, vitamins are of considerable interest in terms of what they do and how they are made. In aLaboratoire de Physiologie Cellulaire Veg´ etale,´ UMR5168, Universite´ Joseph Fourier-CNRS-CEA-INRA, Institut de Recherche en Technologies et the post-genomic era there now exist opportunities to understand Sciences du Vivant, CEA-Grenoble, 17 rue des Martyrs, F-38054, Grenoble, fully how these compounds are synthesised and what their whole Cedex 9, France. E-mail: [email protected]; Fax: +33 438-78-50-91; Tel: +33 cellular functions are. These functions can be quite complex 438-78-44-93 because one particular vitamin may have various metabolic bDepartment of Chemistry, Universite´ Pierre et Marie Curie, UMR CNRS 7613, 75252, Paris, France. E-mail: [email protected] and chemical roles. In addition, this role may fluctuate from cDepartment of Plant Biology, Technical University of Braunschweig, 38106, one organism to another depending on the presence of specific Braunschweig, Germany. E-mail: [email protected] metabolisms (for example photosynthesis in plants). Increasing dDepartment of Plant Sciences, University of Cambridge, Cambridge, CB2 our knowledge concerning their synthesis and function is a prereq- 3EA, UK. E-mail: [email protected] uisite to develop new strategies for health and/or wealth creation, eDepartment of Biochemistry, University of Kent, Canterbury, UK. E-mail: [email protected] including improvement of food quality, design of new antibiotics † This paper was published as part of a themed issue on vitamins and targeting vitamin biosynthesis, and engineering synthesis of new cofactors. compounds. This journal is © The Royal Society of Chemistry 2007 Nat. Prod. Rep., 2007, 24, 949–962 | 949 View Article Online Dr Fabrice Rebeill´ e´ is Director of Research at the Commissariat a` l’Energie Atomique (CEA), Grenoble, France. He graduated from the University of Grenoble where he obtained a Diploma in Pharmacology in 1978 and a PhD in 1983. After a post-doc in Prof. M. D. Hatch’s lab in CSIRO, Canberra, he made a career within the CEA and was also Professor of Biochemistry at the University of Grenoble for four years. His main research activities are focused on plant metabolism, including phosphate metabolism, photosynthesis, photorespiration, and more recently, folate biosynthesis and C1 metabolism. Dr Stephane´ Ravanel is Associate Professor at the University of Grenoble, France. He studied biochemistry and molecular biology at the universities of Lyon and Grenoble, and then completed a PhD in plant biology in 1995. After a post-doc in Prof. Rochaix’s lab at the University of Geneva, he joined the University of Grenoble and the lab of Plant Cell Physiology in 1998. His present research focuses on the molecular, biochemical and regulatory aspects of folate and one-carbon metabolism in plants. Stephane´ Ravanel Fabrice Rebeill´ e´ Here, we will describe, as examples, the role of five coenzymes: folate (vitamin B9), pantothenate (vitamin B5), cobalamin (vita- min B12), biotin (vitamin B8) and molybdenum cofactor (Moco). Firstly, their biological functions will be emphasised, including the specific roles found in some organisms. In the second part we will present some nutritional aspects concerning these coenzymes and potential strategies to enhance the cofactor contents in organisms of interest. 2 Biological functions 2.1 Main functions found in all organisms Published on 20 August 2007. Downloaded by Harvard University 19/11/2013 20:46:55. Cofactors are required in almost all important metabolic path- ways. Because they are specialised in certain types of reaction, one particular cofactor can be involved in several pathways and, conversely, several cofactors can be required in one particular pathway. The following section considers the main areas of metabolism in which the above five coenzymes are involved. 2.1.1 Nucleic acid synthesis: the role of folate. The syntheses of both purine and pyrimidine nucleotides require a folate coenzyme. Folates are involved in ‘one-carbon’ unit (C1 unit) Fig. 1 Chemical structure of THF and major reactions of C1 metabolism. transfer reactions, also called ‘C1 metabolism’. Folate is a generic THF is substituted at the N-5 and/or N-10 positions by C1 units having term that represents a family of molecules (Fig. 1) deriving from various oxidation states. There are generally between 4 and 8 glutamate tetrahydrofolate (5,6,7,8-tetrahydropteroylpolyglutamate, THF). residues. Serine and, to a lesser extent, formate, are the sources of C1 units. Chemically, these folate molecules are composed of a pterin ring, The highest flux of C1 units occurs through methionine synthesis to sustain a p-aminobenzoic acid (pABA) unit and a polyglutamate chain AdoMet turnover and all the methylation reactions, which explains why with a variable number (1 to 14) of glutamate residues.1 Their 5-methyltetrahydrofolate is the dominant folate species. role is to transport and donate C1 units. The C1 units transported by the vitamin arise essentially from the reaction catalyzed by serine hydroxymethyltransferase (SHMT) that converts serine into on the nature of the C1 unit carried, the folate coenzyme will be glycine.2 Formate is also a potential, although minor, source of involved in various pathways (summarised in Fig. 1). Thus, the 3 C1 units. Once attached to the THF body, these C1 units can folate pool is a complex mixture of related molecules differing be reduced or oxidised, from methyl (the most reduced), via in the oxidation state of the pterin ring (di- or tetrahydrofolate), 4 methylene, to formyl or methenyl (the most oxidised). Depending in the oxidation state of the C1 unit carried and in the length of 950 | Nat. Prod. Rep., 2007, 24, 949–962 This journal is © The Royal Society of Chemistry 2007 View Article Online the glutamate chain. Only the most reduced form of the cofactor involved in the de novo synthesis of THF in folate-autotroph 6 (tetrahydrofolate) can transport these C1 units. organisms. Synthesis of the purine ring provides AMP and GMP bases for DNA and RNA strands, as well as for coenzymes such as 2.1.2 The methylation cycle: the roles of folate and cobalamin. NAD(P)+, FAD, CoA and S-adenosylmethionine (AdoMet). In Methionine (Met) is an essential amino acid not only required plants, these nucleotides are also precursors for purine alkaloids for the synthesis of protein but also for the formation of S- and the cytokinin hormones. The pathway for their synthesis is adenosylmethionine (AdoMet), the universal methyl donor and 7,8 similar in plants, animals and micro-organisms.5 It is a complex a key element in the ‘methylation cycle’ (Fig. 3a). In fact, process requiring 13 steps from ribose 5-phosphate. The fourth and 80% of the free Met present in the cell is used in this cycle, tenth steps, respectively catalyzed by glycinamide ribonucleotide whose function is continuously to supply with AdoMet the transformylase and aminoimidazole carboxamide ribonucleotide dozens of methyltransferase enzymes present in all cells.
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