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 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...
cofactors (vitamin B12) in its various forms. In the 21st century, discovery of new systems containing carbon-metal bonds in biology, bioorganometallic chemistry is rapidly emerging as a distinct subdiscipline of
bioinorganic chemistry 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 t ...
that straddles
organometallic chemistry 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 so ...
and
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
. Naturally occurring bioorganometallics include
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s and sensor
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s. 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 Methylmercury (sometimes methyl mercury) is an organometallic cation with the formula . It is the simplest organomercury compound. Methylmercury is extremely toxic, and its derivatives are the major source of organic mercury for humans. It is a ...
). Consequently, bioorganometallic chemistry is increasingly relevant to
medicine Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...
and
pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
.


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 (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
. Carbon monoxide dehydrogenase (CODH) catalyzes the
water–gas shift reaction The water-gas shift reaction (WGSR) describes the reaction of carbon monoxide and water vapor to form carbon dioxide and hydrogen: : CO + H2O CO2 + H2 The water gas shift reaction was discovered by Italian physicist Felice Fontana in 1780. ...
, 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 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...
.
Hydrogenase A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen (H2), as shown below: Hydrogen uptake () is coupled to the reduction of electron acceptors such as oxygen, nitrate, sulfate, carbon dioxide (), and fumarat ...
s are bioorganometallic in the sense that their active sites feature Fe–CO functionalities, although the CO ligands are only spectators. The Fe-only 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 iFehydrogenases are described as (NC)2(OC)Fe(μ-SR)2Ni(SR)2 (where SR is
cysteinyl Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
). The "FeS-free" hydrogenases have an undetermined active site containing an Fe(CO)2 center.
Methanogenesis Methanogenesis or biomethanation is the formation of methane coupled to energy conservation by microbes known as methanogens. Organisms capable of producing methane for energy conservation have been identified only from the domain Archaea, a group ...
, the biosynthesis of methane, entails as its final step, the scission of a
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
–
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
bond in
cofactor F430 F430 is the cofactor (sometimes called the coenzyme) of the enzyme methyl coenzyme M reductase (MCR). MCR catalyzes the reaction that releases methane in the final step of methanogenesis: : + HS–CoB → + CoB–S–S–CoM It is found ...
. The iron–molybdenum cofactor (
FeMoco FeMoco ( 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. Containing iron and molyb ...
) of
nitrogenase Nitrogenases are enzymes () that are produced by certain bacteria, such as cyanobacteria (blue-green bacteria) and rhizobacteria. These enzymes are responsible for the Organic redox reaction, reduction of nitrogen (N2) to ammonia (NH3). Nitrog ...
s contains an Fe6C unit and is an example of an interstitial
carbide In chemistry, a carbide usually describes a compound composed of carbon and a metal. In metallurgy, carbiding or carburizing is the process for producing carbide coatings on a metal piece. Interstitial / Metallic carbides The carbides of the ...
found in biology. 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 The lactate racemase enzyme (Lar) () interconverts the D- and L-enantiomers of lactic acid. It is classified under the isomerase, racemase, epimerase, and enzyme acting on hydroxyl acids and derivatives classes of enzymes. It is found in certain ...
.


In sensor proteins

Some iFecontaining proteins are known to sense H2 and thus regulate transcription.
Copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
-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.
Cyclopropene Cyclopropene is an organic compound with the formula . It is the simplest cycloalkene. Because the ring is highly strained, cyclopropene is difficult to prepare and highly reactive. This colorless gas has been the subject for many fundamental st ...
s inhibit ripening by binding to the copper(I) center. Binding to copper is also implicated in the mammalian olfaction of olefins. 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 Thiomersal (INN), or thimerosal (USAN, JAN), is an organomercury compound. It is a well-established antiseptic and antifungal agent. The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been u ...
) and arsenic (e.g.
Salvarsan Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis. This organoarsenic compound was the fi ...
) had a long history of use in medicine as nonselective antimicrobials before the advent of modern antibiotics.
Titanocene dichloride Titanocene dichloride is the organotitanium compound with the formula ( ''η''5-C5H5)2TiCl2, commonly abbreviated as Cp2TiCl2. This metallocene is a common reagent in organometallic and organic synthesis. It exists as a bright red solid that slowl ...
displays anti-cancer activity, and dichloridobis ''p''-methoxybenzyl)cyclopentadienylitanium is a current anticancer drug candidate.
Arene Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The parent member of aromatic compounds is benzene. The word "aromatic" originates from the past grouping ...
- and
cyclopentadienyl Cyclopentadienyl can refer to *Cyclopentadienyl anion, or cyclopentadienide, **Cyclopentadienyl ligand *Cyclopentadienyl radical, • *Cyclopentadienyl cation, See also *Pentadienyl In organic chemistry, pentadienyl refers to the organic radic ...
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 Motivational salience is a cognitive process and a form of attention that ''motivates'' or propels an individual's behavior towards or away from a particular stimulus (psychology), object, perceived event or outcome. Motivational salience regulat ...
) and habituation, namely with the phenyltropane compound ·6-(2''β''-carbomethoxy-3''β''-phenyl)tropanericarbonylchromium. Carbon monoxide releasing organometallic compounds are also actively investigated, due to the importance of carbon monoxide as a
gasotransmitter Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide ...
.


Toxicology

Within the realm of bioorganometallic chemistry is the study of the fates of synthetic organometallic compounds.
Tetraethyllead Tetraethyllead (commonly styled tetraethyl lead), abbreviated TEL, is an organolead compound with the formula Pb( C2H5)4. It is a fuel additive, first being mixed with gasoline beginning in the 1920s as a patented octane rating booster that al ...
has received considerable attention in this regard as has its successors such as
methylcyclopentadienyl manganese tricarbonyl Methylcyclopentadienyl manganese tricarbonyl (MMT or MCMT) is an organomanganese compound with the formula (C5H4CH3)Mn(CO)3. Initially marketed as a supplement for use in leaded gasoline, MMT was later used in unleaded gasoline to increase the o ...
.
Methylmercury Methylmercury (sometimes methyl mercury) is an organometallic cation with the formula . It is the simplest organomercury compound. Methylmercury is extremely toxic, and its derivatives are the major source of organic mercury for humans. It is a ...
is a particularly infamous case; this cation is produced by the action of vitamin B12-related enzymes on mercury.


References

{{Branches of chemistry Biochemistry Inorganic chemistry Organometallic chemistry Medicinal inorganic chemistry Bioinorganic chemistry