Mechanistic complexities of sulfite oxidase: An enzyme with multiple domains, subunits, and cofactors.

Sulfite oxidase (SO) deficiency, an inherited disease that causes severe neonatal neurological problems and early death, arises from defects in the biosynthesis of the molybdenum cofactor (Moco) (general sulfite oxidase deficiency) or from inborn errors in the SUOX gene for SO (isolated sulfite oxidase deficiency, ISOD). The X-ray structure of the highly homologous homonuclear dimeric chicken sulfite oxidase (cSO) provides a template for locating ISOD mutation sites in human sulfite oxidase (hSO). Catalysis occurs within an individual subunit of hSO, but mutations that disrupt the hSO dimer are pathological.

{Moco}, (n = 0-8): A general formalism for describing the highly covalent molybdenum cofactor of sulfite oxidase and related Mo enzymes.

Over 50 molybdenum enzymes in three distinct families (sulfite oxidase, xanthine oxidase, DMSO reductase) are known, and representative X-ray crystal structures are available for all families. Structural analogues that replicate the coordination about the Mo atom in the absence of surrounding protein have been synthesized and characterized. The properties of metal complexes of non-innocent dithiolene ligands and their oxidized counter parts, dithiones, are summarized.

Metal-Dithiolene Bonding Contributions to Pyranopterin Molybdenum Enzyme Reactivity.

Here we highlight past work on metal-dithiolene interactions and how the unique electronic structure of the metal-dithiolene unit contributes to both the oxidative and reductive half reactions in pyranopterin molybdenum and tungsten enzymes. The metallodithiolene electronic structures detailed here were interrogated using multiple ground and excited state spectroscopic probes on the enzymes and their small molecule analogs. The spectroscopic results have been interpreted in the context of bonding and spectroscopic calculations, and the pseudo-Jahn-Teller effect.

Vibrational Control of Covalency Effects Related to the Active Sites of Molybdenum Enzymes.

A multitechnique spectroscopic and theoretical study of the CpM(benzenedithiolato) (M = Ti, V, Mo; Cp = η-CH) series provides deep insight into dithiolene electronic structure contributions to electron transfer reactivity and reduction potential modulation in pyranopterin molybdenum enzymes. This work explains the magnitude of the dithiolene folding distortion and the concomitant changes in metal-ligand covalency that are sensitive to electronic structure changes as a function of d-electron occupancy in the redox orbital. It is shown that the large fold angle differences correlate with covalency, and the fold angle distortion is due to a pseudo-Jahn-Teller (PJT) effect.

Consensus structures of the Mo(v) sites of sulfite-oxidizing enzymes derived from variable frequency pulsed EPR spectroscopy, isotopic labelling and DFT calculations.

Sulfite-oxidizing enzymes from eukaryotes and prokaryotes have five-coordinate distorted square-pyramidal coordination about the molybdenum atom. The paramagnetic Mo(v) state is easily generated, and over the years four distinct CW EPR spectra have been identified, depending upon enzyme source and the reaction conditions, namely high and low pH (hpH and lpH), phosphate inhibited (P) and sulfite (or blocked). Extensive studies of these paramagnetic forms of sulfite-oxidizing enzymes using variable frequency pulsed electron spin echo (ESE) spectroscopy, isotopic labeling and density functional theory (DFT) calculations have led to the consensus structures that are described here.