Wikipedia

Bioorganometallic chemistry

Bioorganometallic chemistry is the study of biologically active molecules that contain carbon directly bonded to metals or metalloids. The importance of main-group and transition-metal centers has long been recognized as important to the function of enzymes and other biomolecules. However, only a small subset of naturally-occurring metal complexes and synthetically prepared pharmaceuticals are organometallic; that is, they feature a direct covalent bond between the metal(loid) and a carbon atom. The first, and for a long time, the only examples of naturally occurring bioorganometallic compounds were the cobalamin cofactors (vitamin B12) in its various forms.[1] In the 21st century, as a result of the discovery of new systems containing carbon–metal bonds in biology, bioorganometallic chemistry is rapidly emerging as a distinct subdiscipline of bioinorganic chemistry that straddles organometallic chemistry and biochemistry. Naturally occurring bioorganometallics include enzymes and sensor proteins. Also within this realm are synthetically prepared organometallic compounds that serve as new drugs and imaging agents (technetium-99m sestamibi) as well as the principles relevant to the toxicology of organometallic compounds (e.g., methylmercury).[2][3] Consequently, bioorganometallic chemistry is increasingly relevant to medicine and pharmacology.[4]

In cofactors and prosthetic groups

edit

Vitamin B12 is the preeminent bioorganometallic species. Vitamin B12 is actually a collection of related enzyme cofactors, several of which contain cobalt–alkyl bonds, and is involved in biological methylation and 1,2-carbon rearrangement reactions. For a long time since its structure was elucidated by Hodgkin in 1955, it was believed to be the only example of a naturally occurring bioorganometallic system.

Several bioorganometallic enzymes carry out reactions involving carbon monoxide. Carbon monoxide dehydrogenase (CODH) catalyzes the water–gas shift reaction, which provides CO (through a nickelacarboxylate intermediate) for the biosynthesis of acetylcoenzyme A. The latter step is effected by the Ni–Fe enzyme CO-methylating acetyl-CoA synthase (ACS). CODH and ACS often occur together in a tetrameric complex, the CO being transported via a tunnel and the methyl group being provided by methyl cobalamin.

Hydrogenases are bioorganometallic in the sense that their active sites feature Fe–CO functionalities, although the CO ligands are only spectators.[5] The binuclear [FeFe]-hydrogenases have a Fe2(μ-SR)2(μ-CO)(CO)2(CN)2 active site connected to a 4Fe4S cluster via a bridging thiolate. The active site of the [NiFe]-hydrogenases are described as (NC)2(OC)Fe(μ-SR)2Ni(SR)2 (where SR is cysteinyl).[6] Mononuclear [Fe]-hydrogenases contain an Fe(CO)2(SR)(LX) active site, where LX is a 6-acylmethyl-2-pyridinol ligand, bound to the Fe center through the pyridyl nitrogen (L) and the acyl carbon (X).[7][8] This class of hydrogenases thus provides examples of naturally occurring iron acyl complexes.

Methanogenesis, the biosynthesis of methane, entails as its final step, the scission of a nickel–methyl bond in cofactor F430.

The iron–molybdenum cofactor (FeMoco) of nitrogenases contains an Fe6C unit and is an example of an interstitial carbide found in biology.[9][10]

The first example of a naturally-occurring arylmetal species, a pincer complex containing a nickel–aryl bond, has been reported to form the active site of lactate racemase.[11]

In sensor proteins

edit

Some [NiFe]-containing proteins are known to sense H2 and thus regulate transcription.

Copper-containing proteins are known to sense ethylene, which is known to be a hormone relevant to the ripening of fruit. This example illustrates the essential role of organometallic chemistry in nature, as few molecules outside of low-valent transition metal complexes reversibly bind alkenes. Cyclopropenes inhibit ripening by binding to the copper(I) center. Binding to copper is also implicated in the mammalian olfaction of olefins.[12]

Carbon monoxide occurs naturally and is a transcription factor via its complex with a sensor protein based on ferrous porphyrins.

In medicine

edit

Organometallic compounds containing mercury (e.g., thiomersal) and arsenic (e.g. Salvarsan) had a long history of use in medicine as nonselective antimicrobials before the advent of modern antibiotics.

Titanocene dichloride displays anti-cancer activity, and dichloridobis[(p-methoxybenzyl)cyclopentadienyl]titanium is a current anticancer drug candidate. Arene- and cyclopentadienyl complexes are kinetically inert platforms for the design of new radiopharmaceuticals.

Furthermore, there have been made studies utilizing exogenous semi-synthetic ligands; specifically to the dopamine transporter, observing increased resultant efficacy in regard to reward facilitating behavior (incentive salience) and habituation, namely with the phenyltropane compound [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium.

Carbon monoxide releasing organometallic compounds are also actively investigated, due to the importance of carbon monoxide as a gasotransmitter.

Toxicology

edit

Within the realm of bioorganometallic chemistry is the study of the fates of synthetic organometallic compounds. Tetraethyllead has received considerable attention in this regard as has its successors such as methylcyclopentadienyl manganese tricarbonyl. Methylmercury is a particularly infamous case; this cation is produced by the action of vitamin B12-related enzymes on mercury.

References

edit
  1. ^ Hodgkin DG, Pickworth J, Robertson JH, Trueblood KN, Prosen RJ, White JG (August 1955). "The crystal structure of the hexacarboxylic acid derived from B12 and the molecular structure of the vitamin". Nature. 176 (4477): 325–328. Bibcode:1955Natur.176..325H. doi:10.1038/176325a0. PMID 13253565. S2CID 4220926.
  2. ^ Sigel A, Sigel H, Sigel RK, eds. (2009). Metal-carbon bonds in enzymes and cofactors. Metal Ions in Life Sciences. Vol. 6. Royal Society of Chemistry. ISBN 978-1-84755-915-9.
  3. ^ Linck RC, Rauchfuss TB (2005). "Synthetic Models for Bioorganometallic Reaction Centers". In Jaouen G (ed.). Bioorganometallics: Biomolecules, Labeling, Medicine. Weinheim: Wiley-VCH. pp. 403–435. doi:10.1002/3527607692.ch12. ISBN 978-3-527-30990-0.
  4. ^ Jaouen G (2006). Bioorganometallics : biomolecules, labeling, medicine. Weinheim: Wiley-VCH. ISBN 3527607692. OCLC 85821090.
  5. ^ Cammack R, Frey M, Robson R (2001). Hydrogen as a Fuel: Learning from Nature. London: Taylor & Francis. ISBN 978-0-415-24242-4.
  6. ^ Volbeda A, Fontecilla-Camps JC (2003). "The Active Site and Catalytic Mechanism of NiFe Hydrogenases". Dalton Transactions (21): 4030–4038. doi:10.1039/B304316A.
  7. ^ Hiromoto T, Ataka K, Pilak O, Vogt S, Stagni MS, Meyer-Klaucke W, et al. (February 2009). "The crystal structure of C176A mutated [Fe]-hydrogenase suggests an acyl-iron ligation in the active site iron complex". FEBS Letters. 583 (3): 585–590. doi:10.1016/j.febslet.2009.01.017. PMID 19162018. S2CID 1055079.
  8. ^ Schaupp S, Arriaza-Gallardo FJ, Pan HJ, Kahnt J, Angelidou G, Paczia N, et al. (May 2022). "In Vitro Biosynthesis of the [Fe]-Hydrogenase Cofactor Verifies the Proposed Biosynthetic Precursors". Angewandte Chemie. 61 (22): e202200994. doi:10.1002/anie.202200994. PMC 9314073. PMID 35286742.
  9. ^ Spatzal T, Aksoyoglu M, Zhang L, Andrade SL, Schleicher E, Weber S, et al. (November 2011). "Evidence for interstitial carbon in nitrogenase FeMo cofactor". Science. 334 (6058): 940. Bibcode:2011Sci...334..940S. doi:10.1126/science.1214025. PMC 3268367. PMID 22096190.
  10. ^ Lancaster KM, Roemelt M, Ettenhuber P, Hu Y, Ribbe MW, Neese F, et al. (November 2011). "X-ray emission spectroscopy evidences a central carbon in the nitrogenase iron-molybdenum cofactor". Science. 334 (6058): 974–977. Bibcode:2011Sci...334..974L. doi:10.1126/science.1206445. PMC 3800678. PMID 22096198.
  11. ^ Rankin JA, Mauban RC, Fellner M, Desguin B, McCracken J, Hu J, et al. (June 2018). "Lactate Racemase Nickel-Pincer Cofactor Operates by a Proton-Coupled Hydride Transfer Mechanism". Biochemistry. 57 (23): 3244–3251. doi:10.1021/acs.biochem.8b00100. OSTI 1502215. PMID 29489337.
  12. ^ Duan X, Block E, Li Z, Connelly T, Zhang J, Huang Z, et al. (February 2012). "Crucial role of copper in detection of metal-coordinating odorants". Proceedings of the National Academy of Sciences of the United States of America. 109 (9): 3492–3497. Bibcode:2012PNAS..109.3492D. doi:10.1073/pnas.1111297109. PMC 3295281. PMID 22328155.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Bioorganometallic_chemistry&oldid=1256600305"