Molybdenum and Tungsten Cofactors and the Reactions They Catalyze

Abstract

The last 20 years have seen a dramatic increase in our mechanistic understanding of the reactions catalyzed by pyranopterin Mo and W enzymes. These enzymes possess a unique cofactor (Moco) that contains a novel ligand in bioinorganic chemistry, the pyranopterin ene-1,2-dithiolate. A synopsis of Moco biosynthesis and structure is presented, along with our current understanding of the role Moco plays in enzymatic catalysis. Oxygen atom transfer (OAT) reactivity is discussed in terms of breaking strong metal-oxo bonds and the mechanism of OAT catalyzed by enzymes of the sulfite oxidase (SO) family that possess dioxo Mo(VI) active sites. OAT reactivity is also discussed in members of the dimethyl sulfoxide (DMSO) reductase family, which possess des-oxo Mo(IV) sites. Finally, we reveal what is known about hydride transfer reactivity in xanthine oxidase (XO) family enzymes and the formate dehydrogenases. The formal hydride transfer reactivity catalyzed by xanthine oxidase family enzymes is complex and cleaves substrate C-H bonds using a mechanism that is distinct from monooxygenases. The chapter primarily highlights developments in the field that have occurred since ~2000, which have contributed to our collective structural and mechanistic understanding of the three canonical pyranopterin Mo enzymes families: XO, SO, and DMSO reductase.

Figure 1.

The Moco biosynthesis pathway. Relevent intermediates are shown, along with the human proteins that catalyze the individual reactions (adapted from [57]).

Figure 2.

Proposed mechanism for sulfur incorporation (as sulfido) in the human Mo cofactor sulfurase (HMCS). The HMCS modified cofactor can then be incorporated into apo enzyme forms of the xanthine oxidase family.

Figure 3.

Structure of chicken liver sulfite oxidase (PDB 1SOX).

Figure 4.

Proposed mechanism for sulfite oxidase consistent with spectroscopic and computational studies.

Figure 5.

Structure of oxidized dimethylsulfoxide reductase showing apical oxo, serine oxygen, and bis-MGD dithiolene coordination (PDB 1eu1).

Figure 6.

Proposed mechanism for DMSO reductase. Note that the high-g split intermediate is located here on the catalytic pathway in the reductive half reaction of the catalytic cycle (adapted from [171]).

Figure 7.

Structure of product-bound bovine xanthine dehydrogenase (PDB IV97). The structure shows the coordinated MPT, apical oxo, and equatorial sulfhydryl ligands. The inhibitor FYX-051 is bound in the equatorial position that would normally be occupied by hydroxide in oxidized enzyme.

Figure 8.

Paramagnetic Mo(V) forms of xanthine oxidase. The very rapid species is a true enzyme intermediate observed under specific reaction conditions and is a product bound species. Formaldehyde inhibited xanthine oxidase possesses a tetrahedral carbon center and serves as a mimic of the Mo-O-R interaction present in the catalytic cycle of the enzyme. Rapid is a paramagnetic analog of the Michaelis complex and the slow form is a paramagnetic desulfo form of the enzyme that lacks the terminal sulfido-based ligand.

Figure 9.

Proposed mechanism for xanthine oxidase. Note that IM1/TS possesses the tetrahedral-type carbon found in formaldehyde inhibited. IM2 is the reduced Mo(IV) analog of very rapid. The role of the active site glutamate, E1261, is shown.