PERSPECTIVES in a number of enzymes such as [FeFe]- hydrogenase, [FeNi]-hydrogenase, Natural inspirations for metal–ligand [Fe]-hydrogenase, lactate racemase and alcohol dehydrogenase. In this Perspective, cooperative catalysis we discuss these examples of biological cooperative catalysis and how, inspired by these naturally occurring systems, chemists Matthew D. Wodrich and Xile Hu have sought to create functional analogues. Abstract | In conventional homogeneous catalysis, supporting ligands act as We also speculate that cooperative catalysis spectators that do not interact directly with substrates. However, in metal–ligand may be at play in [NiFe]-carbon monoxide cooperative catalysis, ligands are involved in facilitating reaction pathways that dehydrogenase ([NiFe]-CODHase), which may inspire the design of synthetic CO2 would be less favourable were they to occur solely at the metal centre. This reduction catalysts making use of these catalysis paradigm has been known for some time, in part because it is at play motifs. Each section in the following in enzyme catalysis. For example, studies of hydrogenative and dehydrogenative discussion is devoted to an enzyme and its enzymes have revealed striking details of metal–ligand cooperative catalysis synthetic models. that involve functional groups proximal to metal active sites. In addition to [FeFe]- and [NiFe]-hydrogenase the more well-known [FeFe]-hydrogenase and [NiFe]-hydrogenase enzymes, Hydrogenases are enzymes that catalyse [Fe]-hydrogenase, lactate racemase and alcohol dehydrogenase each makes use (REF. 5) the production and utilization of H2 . of cooperative catalysis. This Perspective highlights these enzymatic examples of Three variants of hydrogenase enzymes exist metal–ligand cooperative catalysis and describes functional bioinspired which are named [FeFe]-, [NiFe]- and [Fe]-hydrogenase because their active molecular catalysts that also make use of these motifs. Although progress has 6 been made in developing molecular catalysts, considerable challenges will need sites feature these catalytic metals . The metal centres in both [FeFe]- and to be addressed before we have synthetic catalysts of practical value. [NiFe]-hydrogenase are coordinated to cysteine residues and small inorganic The field of catalysis, broadly defined, attracts designs of new synthetic catalysts, wherein (CO and CN−) ligands that interact with the considerable attention in both academia and both the metal centre(s) and the surrounding surrounding protein environment through industry. To most chemists, homogeneous abiotic ligands act to mediate an otherwise hydrogen-bonding interactions (FIG. 1a,b). catalysis has historically been considered slow reaction. Among other aspects, some Each of the three different active sites to involve one or two metal atoms to which perceived kinetic advantages of cooperative features one metal coordination site that is + ligands are attached. These ligands shape catalysis include the creation of an additional accessible for the binding of either H2 or H the catalytic environment both physically, substrate binding site, the possibility of substrates, with H+ substrates being bound through steric and other noncovalent having Lewis and/or Brønsted acidic and in the form of a hydride7. Certain structural interactions, and electronically, through basic sites within the same catalyst and the moieties, such as the bis(sulfidomethyl) − inductive and resonance effects on the metal preorganization of the transition state. amine (azadithiolate, HN(CH2S )2) ligand centre (BOX 1). Traditionally, the ligands are Metal–ligand cooperation has long been in [FeFe]-hydrogenase8,9 and the terminal not directly involved in the reaction that is recognized as being central to the function cysteine residues in [NiFe]-hydrogenase10, being catalysed, which occurs only at the of metalloproteins, with one prominent have long been implicated as internal + metal centre. Enzymatic catalysis typically example being the binding of O2 in bases — groups that relay H and facilitate 6 takes advantage of more sophisticated myoglobin, wherein a distal histidine residue H2 activation or production . These two processes for facilitating the chemical forms a hydrogen bond to Fe-coordinated O2. enzymes, which interconvert H2, protons and reactions that are essential for life. Once This motif has been replicated in synthetic electrons, are now described in terms of these again, they tend to feature one or more metal systems that feature so-called picket-fence second coordination sphere effects. atoms surrounded by a sphere of ligands, and picnic-basket porphyrinato complexes Elegant studies involving the insertion of which may take the form of amino acids, decorated with hydrogen-bond donors3,4. synthetic mimics of the [FeFe]-hydrogenase organic cofactors and other typical inorganic However, beyond hydrogen bonding, direct active site into the cofactor-free apo-form ligands. However, many enzymes have ligand participation in bond-breaking and of [FeFe]-hydrogenase have afforded evolved to make use of both the metal centre bond-forming steps in enzyme catalysis has semisynthetic enzymes with varying and the surrounding ligand environment only begun to be elucidated. Recent studies activities11–15. Full activity of the native in performing catalysis (BOX 1). Referred have revealed or confirmed that such ligand enzyme was achieved only by the use of a to as ‘cooperative catalysis’ (REFS 1,2), this participation helps allow for hydrogen mimic that features an azadithiolate ligand paradigm can also be incorporated into metabolism and dehydrogenation reactions bridging two Fe centres. This result indirectly NATURE REVIEWS | CHEMISTRY VOLUME 2 | ARTICLE NUMBER 0099 | 1 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. PERSPECTIVES Box 1 | Classical and cooperative catalysis the 2-methoxy-containing cofactor cannot perform. As a result, the enzyme In classical transition metal catalysis (see the figure, part a), only the metal is involved in the reconstituted using 2 is unable to access reaction, with the ligand(s) serving mainly to engender certain electronic and steric properties on a low-energy pathway to H heterolysis, the metal centre. In cooperative catalysis (see the figure, part b), both the metal centre and one or 2 such that it has no detectable activity. more ligands are directly involved in the reactions. Interactions with the substrate may involve hydrogen bonding, dative bonding and/or electrostatic interactions. The reconstitution study provides further evidence that [Fe]-hydrogenase operates a b through cooperative catalysis in which a Substrate(s) M L Substrate(s) M L second coordination sphere heteroatom- containing group acts as an internal base. Many early synthetic models for [Fe]- hydrogenase, some closely resembling L, ligand; M, metal the active site of the native enzyme, were Nature Reviews | Chemistry unable to catalyse either H2 heterolysis or activation24. Guided by mechanistic insights confirms the presence of this ligand in Thus, akin to the [NiFe]- and [FeFe]- from the reconstitution studies, we used the active site of the [FeFe]-hydrogenases, hydrogenases, [Fe]-hydrogenase also density functional theory computations to providing strong evidence that the H2 participates in cooperative catalysis by predict the activity of several synthetically formation and oxidation mechanisms means of functional groups in its second viable biomimetic complexes, finding that involve the azadithiolate amine in the second coordination sphere that relay H+. species bearing a pendant amine were most + (REF. 25) coordination sphere relaying H to and The [Fe]-hydrogenase holoenzyme likely to activate H2 . A close analogue from the active site (FIG. 1a). A similar study can be reconstituted from its apo-enzyme of the most promising computational model on [NiFe]-hydrogenase10 used site-directed and the isolated cofactor. This gave was synthesized, with this catalyst candidate mutagenesis to show that a N atom in a synthetic chemists hope that artificial featuring biomimetic pyridinylacyl and CO strictly conserved arginine residue acts as cofactors might also be amenable to the ligands in addition to a diphosphine ligand 26 FIG. 2e a general base for H2 activation. Nature reconstitution procedure and afford new with a noncoordinated amine (3, ). judiciously places this atom 4.5 Å above the Fe species with potentially high activities. Such The amine–diphosphine, although not and Ni centres in the enzyme, the bimetallic semisynthetic enzymes provide an ideal tool structurally relevant to [Fe]-hydrogenase, site that eventually receives the substrate, in for studying the mechanistic role played is bioinspired in that it is reminiscent of the this case in the form of H− (FIG. 1b). Although by ancillary moieties located in the second azadithiolate cofactor in [FeFe]-hydrogenase. the role of azadithiolate as a proximal base coordination sphere. One such structure– Thus, the amine–diphosphine serves as a H+ in [FeFe]-hydrogenases has been firmly function relationship was uncovered by acceptor in the heterolytic activation of H2 established6,9, the analogous role of Arg509 in preparing semisynthetic [Fe]-hydrogenases by cooperative catalysis. The presence of an the [NiFe]-hydrogenase catalytic mechanism by use of the synthetic model complexes 1 exotic and abiological amine–diphosphine is only a recent proposal that awaits further and 2 (REF. 23) (FIG. 2c). Although neither