Bioorganometallic chemistry

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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]

Contents

In cofactors and prosthetic groups

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

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

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

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.

Related Research Articles

<span class="mw-page-title-main">Organic compound</span> Carbon-containing chemical compound

Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-containing compounds such as alkanes and its derivatives are universally considered organic, but many others are sometimes considered inorganic, such as halides of carbon without carbon-hydrogen and carbon-carbon bonds, and certain compounds of carbon with nitrogen and oxygen.

<span class="mw-page-title-main">Organometallic chemistry</span> Study of organic compounds containing metal(s)

Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and sometimes broadened to include metalloids like boron, silicon, and selenium, as well. Aside from bonds to organyl fragments or molecules, bonds to 'inorganic' carbon, like carbon monoxide, cyanide, or carbide, are generally considered to be organometallic as well. Some related compounds such as transition metal hydrides and metal phosphine complexes are often included in discussions of organometallic compounds, though strictly speaking, they are not necessarily organometallic. The related but distinct term "metalorganic compound" refers to metal-containing compounds lacking direct metal-carbon bonds but which contain organic ligands. Metal β-diketonates, alkoxides, dialkylamides, and metal phosphine complexes are representative members of this class. The field of organometallic chemistry combines aspects of traditional inorganic and organic chemistry.

<span class="mw-page-title-main">Metalloprotein</span> Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

<span class="mw-page-title-main">Nitrogenase</span> Class of enzymes

Nitrogenases are enzymes (EC 1.18.6.1EC 1.19.6.1) that are produced by certain bacteria, such as cyanobacteria (blue-green bacteria) and rhizobacteria. These enzymes are responsible for the reduction of nitrogen (N2) to ammonia (NH3). Nitrogenases are the only family of enzymes known to catalyze this reaction, which is a step in the process of nitrogen fixation. Nitrogen fixation is required for all forms of life, with nitrogen being essential for the biosynthesis of molecules (nucleotides, amino acids) that create plants, animals and other organisms. They are encoded by the Nif genes or homologs. They are related to protochlorophyllide reductase.

Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those that are non-essential, in medicine and toxicology. Many biological processes such as respiration depend upon molecules that fall within the realm of inorganic chemistry. The discipline also includes the study of inorganic models or mimics that imitate the behaviour of metalloproteins.

Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.

<span class="mw-page-title-main">Metal carbonyl</span> Coordination complexes of transition metals with carbon monoxide ligands

Metal carbonyls are coordination complexes of transition metals with carbon monoxide ligands. Metal carbonyls are useful in organic synthesis and as catalysts or catalyst precursors in homogeneous catalysis, such as hydroformylation and Reppe chemistry. In the Mond process, nickel tetracarbonyl is used to produce pure nickel. In organometallic chemistry, metal carbonyls serve as precursors for the preparation of other organometallic complexes.

<span class="mw-page-title-main">Molybdopterin</span> Heterocyclic ligand that can complex molybdenum to form a Mo-cofactor

Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopterin itself contains no molybdenum; rather, this is the name of the ligand that will bind the active metal. After molybdopterin is eventually complexed with molybdenum, the complete ligand is usually called molybdenum cofactor.

<span class="mw-page-title-main">Methylcobalamin</span> Form of vitamin B12

Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of a compound that contains metal–alkyl bonds. Nickel–methyl intermediates have been proposed for the final step of methanogenesis.

<span class="mw-page-title-main">Methylmalonyl-CoA</span> Chemical compound

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle.

A hydrogenase mimic or bio-mimetic is an enzyme mimic of hydrogenases.

In enzymology, carbon monoxide dehydrogenase (CODH) (EC 1.2.7.4) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">5,10-Methenyltetrahydromethanopterin hydrogenase</span> Class of enzymes

The 5,10-methenyltetrahydromethanopterin hydrogenase, the so-called iron-sulfur cluster-free hydrogenase, is an enzyme found in methanogenic archea such as Methanothermobacter marburgensis. It was discovered and first characterized by the Thauer group at the Max Planck Institute in Marburg. Hydrogenases are enzymes that either reduce protons or oxidize molecular dihydrogen.

<span class="mw-page-title-main">Organocobalt chemistry</span> Chemistry of compounds with a carbon to cobalt bond

Organocobalt chemistry is the chemistry of organometallic compounds containing a carbon to cobalt chemical bond. Organocobalt compounds are involved in several organic reactions and the important biomolecule vitamin B12 has a cobalt-carbon bond. Many organocobalt compounds exhibit useful catalytic properties, the preeminent example being dicobalt octacarbonyl.

Organoiron chemistry is the chemistry of iron compounds containing a carbon-to-iron chemical bond. Organoiron compounds are relevant in organic synthesis as reagents such as iron pentacarbonyl, diiron nonacarbonyl and disodium tetracarbonylferrate. Although iron is generally less active in many catalytic applications, it is less expensive and "greener" than other metals. Organoiron compounds feature a wide range of ligands that support the Fe-C bond; as with other organometals, these supporting ligands prominently include phosphines, carbon monoxide, and cyclopentadienyl, but hard ligands such as amines are employed as well.

Marcetta York Darensbourg is an American inorganic chemist. She is a Distinguished Professor of Chemistry at Texas A&M University. Her current work focuses on iron hydrogenases and iron nitrosyl complexes.

<span class="mw-page-title-main">FeMoco</span> Cofactor of nitrogenase

FeMoco (FeMo cofactor) is the primary cofactor of nitrogenase. Nitrogenase is the enzyme that catalyzes the conversion of atmospheric nitrogen molecules N2 into ammonia (NH3) through the process known as nitrogen fixation. Because it contains iron and molybdenum, the cofactor is called FeMoco. Its stoichiometry is Fe7MoS9C.

<span class="mw-page-title-main">CO-methylating acetyl-CoA synthase</span> Enzyme

Acetyl-CoA synthase (ACS), not to be confused with acetyl-CoA synthetase or acetate-CoA ligase, is a nickel-containing enzyme involved in the metabolic processes of cells. Together with carbon monoxide dehydrogenase (CODH), it forms the bifunctional enzyme Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase (ACS/CODH) found in anaerobic microorganisms such as archaea and bacteria. The ACS/CODH enzyme works primarily through the Wood–Ljungdahl pathway which converts carbon dioxide to Acetyl-CoA. The recommended name for this enzyme is CO-methylating acetyl-CoA synthase.

Evolution of metal ions in biological systems refers to the incorporation of metallic ions into living organisms and how it has changed over time. Metal ions have been associated with biological systems for billions of years, but only in the last century have scientists began to truly appreciate the scale of their influence. Major and minor metal ions have become aligned with living organisms through the interplay of biogeochemical weathering and metabolic pathways involving the products of that weathering. The associated complexes have evolved over time.

<span class="mw-page-title-main">Transition metal acyl complexes</span>

Transition metal acyl complexes describes organometallic complexes containing one or more acyl (RCO) ligands. Such compounds occur as transient intermediates in many industrially useful reactions, especially carbonylations.

References

  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.
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