INTRODUCTION Charles G. Riordan Acetyl coenzyme A synthase: new insights into one of Nature’s bioorganometallic catalysts Received: 21 May 2004 / Accepted: 21 May 2004 / Published online: 23 June 2004 Ó SBIC 2004 Keywords Iron-sulfur clusters Æ Nickel Æ Organometallic complexes The Ni-Fe-S proteins carbon monoxide dehydrogenase (COdH) and acetyl coenzyme A synthase (ACS) are enzymes crucial to the global carbon cycle, as they interconvert C 1 entities, CO 2 , CO, and CH 3 equivalent, via redox reactions that allow certain archae and eu- bacteria to grow autotrophically, fixing CO 2 via the Wood–Ljungdahl pathway for their anabolic metabo- lism [1]. The ancestry of the organisms may be traced to the time of the origin of life, with these enzymes repre- senting Nature’s earliest catalysts [2]. The redox reac- tions promoted by COdH and ACS, Eqs. 1 and 2, are reminiscent of the industrial water-gas shift and Mons- anto acetic acid synthesis reactions, respectively, that may serve to connect the biological and organometallic communities while expanding the bioorganometallic paradigm beyond B 12 chemistry [3]: CO þ H 2 O  CO 2 þ 2H þ þ 2e  ð1Þ CH 3 - cob III ð Þalamin þ CO þ HSCoA  CH 3 CO ð ÞSCoA þ cob I ðÞalamin ð2Þ Recent high-resolution X-ray structure reports have revealed molecular level details of the active site com- positions responsible for catalysis [4, 5, 6]. Quite sur- prisingly, in two independent structures from the same acetogenic organism, Moorella thermoacetica, the active site responsible for ACS activity, cluster A, was found to have different metal ion compositions. The ensuing debate surrounding the identity of the metals responsible for activity has energized the bioinorganic community. More generally, the structural results have served to highlight fundamental questions of how the metal clus- ter structure encodes function for acetate biosynthesis. While details of the mechanism of ACS remain to be established, it appears clear that novel enzyme-bound intermediates are involved. Specifically, organometallic functional groups, i.e. metal-bound CO, CH 3 , and C(O)CH 3 ligands, are interconverted on the A cluster. A canonical mechanism (see Scheme 1) is emerging that provides a framework for productive discussion and debate, as well as for directing further experiments. Details of the molecular (site of ligand binding) and electronic structure, including metal ion oxidation states, of the various intermediates have yet to be established. Further, the order of the first two steps, CO and CH 3 binding, is not certain. In this series of Commentaries, the structure, spec- troscopic properties, enzyme mechanism, and synthetic analog chemistry of acetyl coenzyme A synthase are reviewed. The collection serves to highlight the successes of highly interdisciplinary approaches to common scientific questions in bioinorganic chemistry. References 1. Wood HG, Ljungdahl LG (1991) In: Shively JM, Barton LL (eds) Variations in autotrophic life. Academic Press, New York, pp 201–250 2. Huber C, Wachtershauser G (1997) Science 276:245–247 3. Riordan CG (2003) In: McCleverty J, Meyer TJ (eds) Compre- hensive coordination chemistry II, vol 8. Elsevier, Oxford, pp 677–713 4. Doukov TI, Iverson TM, Seravalli J, Ragsdale SW, Drennan CL (2002) Science 298:567–572 5. Darnault C, Volbeda A, Kim EJ, Legrand P, Vernede X, Lindahl PA, Fontecilla-Camps JC (2003) Nat Struct Biol 10:271–279 6. Svetlitchnyi V, Dobbek H, Meyer-Klaucke W, Meins T, Thiele B, Romer P, Huber R, Meyer O (2004) Proc Natl Acad Sci USA 101:446–451 C. G. Riordan Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA E-mail: riordan@udel.edu Fax: +1-302-8316335 J Biol Inorg Chem (2004) 9: 509–510 DOI 10.1007/s00775-004-0562-z