Sulfite oxidase explained

sulfite oxidase
Ec Number:	1.8.3.1
Cas Number:	9029-38-3
Go Code:	0008482
Width:	292px

Sulfite oxidase is an enzyme in the mitochondria of all eukaryotes, with exception of the yeasts. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ATP in oxidative phosphorylation.^{[1] [2] [3]} This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

Sulfite oxidase is a metallo-enzyme that utilizes a molybdopterin cofactor and a heme group (in the case of animals). It is one of the cytochromes b₅ and belongs to the enzyme super-family of molybdenum oxotransferases that also includes DMSO reductase, xanthine oxidase, and nitrite reductase.

In mammals, the expression levels of sulfite oxidase is high in the liver, kidney, and heart, and very low in spleen, brain, skeletal muscle, and blood.

Structure

As a homodimer, sulfite oxidase contains two identical subunits with an N-terminal domain and a C-terminal domain. These two domains are connected by ten amino acids forming a loop. The N-terminal domain has a heme cofactor with three adjacent antiparallel beta sheets and five alpha helices. The C-terminal domain hosts a molybdopterin cofactor that is surrounded by thirteen beta sheets and three alpha helices. The molybdopterin cofactor has a Mo(VI) center, which is bonded to a sulfur from cysteine, an ene-dithiolate from pyranopterin, and two terminal oxygens. It is at this molybdenum center that the catalytic oxidation of sulfite takes place.

The pyranopterin ligand which coordinates the molybdenum centre via the enedithiolate. The molybdenum centre has a square pyramidal geometry and is distinguished from the xanthine oxidase family by the orientation of the oxo group facing downwards rather than up.

Active site and mechanism

The active site of sulfite oxidase contains the molybdopterin cofactor and supports molybdenum in its highest oxidation state, +6 (Mo^VI). In the enzyme's oxidized state, molybdenum is coordinated by a cysteine thiolate, the dithiolene group of molybdopterin, and two terminal oxygen atoms (oxos). Upon reacting with sulfite, one oxygen atom is transferred to sulfite to produce sulfate, and the molybdenum center is reduced by two electrons to Mo^IV. Water then displaces sulfate, and the removal of two protons (H⁺) and two electrons (e⁻) returns the active site to its original state. A key feature of this oxygen atom transfer enzyme is that the oxygen atom being transferred arises from water, not from dioxygen (O₂).

Electrons are passed one at a time from the molybdenum to the heme group which reacts with cytochrome c to reoxidize the enzyme. The electrons from this reaction enter the electron transport chain (ETC).

This reaction is generally the rate limiting reaction. Upon reaction of the enzyme with sulfite, it is reduced by 2 electrons. The negative potential seen with re-reduction of the enzyme shows the oxidized state is favoured.

Among the Mo enzyme classes, sulfite oxidase is the most easily oxidized. Although under low pH conditions the oxidative reaction become partially rate limiting.

Deficiency

Sulfite oxidase is required to metabolize the sulfur-containing amino acids cysteine and methionine in foods. Lack of functional sulfite oxidase causes a disease known as sulfite oxidase deficiency. This rare but fatal disease causes neurological disorders, mental retardation, physical deformities, the degradation of the brain, and death. Reasons for the lack of functional sulfite oxidase include a genetic defect that leads to the absence of a molybdopterin cofactor and point mutations in the enzyme.^[4] A G473D mutation impairs dimerization and catalysis in human sulfite oxidase.^{[5] [6]}

See also

• Sulfur metabolism
• Bioinorganic chemistry

Further reading

• Kisker, C. “Sulfite oxidase”, Messerschimdt, A.; Huber, R.; Poulos, T.; Wieghardt, K.; eds. Handbook of Metalloproteins, vol 2; John Wiley and Sons, Ltd: New York, 2002
• Feng C, Wilson HL, Hurley JK, etal . Essential role of conserved arginine 160 in intramolecular electron transfer in human sulfite oxidase. . Biochemistry . 42 . 42 . 12235–42 . 2003 . 14567685 . 10.1021/bi0350194 .
• Lee HF, Mak BS, Chi CS, etal . A novel mutation in neonatal isolated sulphite oxidase deficiency. . Neuropediatrics . 33 . 4 . 174–9 . 2002 . 12368985 . 10.1055/s-2002-34491 . 39922068 .
• Steinberg KK, Relling MV, Gallagher ML, etal . Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada. . Environ. Health Perspect. . 115 . 1 . 158–64 . 2007 . 17366837 . 10.1289/ehp.9025 . 1817665 .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 .
• Wilson HL, Wilkinson SR, Rajagopalan KV . The G473D mutation impairs dimerization and catalysis in human sulfite oxidase. . Biochemistry . 45 . 7 . 2149–60 . 2006 . 16475804 . 10.1021/bi051609l .
• Hoffmann C, Ben-Zeev B, Anikster Y, etal . Magnetic resonance imaging and magnetic resonance spectroscopy in isolated sulfite oxidase deficiency. . J. Child Neurol. . 22 . 10 . 1214–21 . 2007 . 17940249 . 10.1177/0883073807306260 . 24050167 .
• Johnson JL, Coyne KE, Garrett RM, etal . Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients. . Hum. Mutat. . 20 . 1 . 74 . 2002 . 12112661 . 10.1002/humu.9038 . 45465780 . free .
• Woo WH, Yang H, Wong KP, Halliwell B . Sulphite oxidase gene expression in human brain and in other human and rat tissues. . Biochem. Biophys. Res. Commun. . 305 . 3 . 619–23 . 2003 . 12763039 . 10.1016/S0006-291X(03)00833-7 .
• Feng C, Wilson HL, Tollin G, etal . The pathogenic human sulfite oxidase mutants G473D and A208D are defective in intramolecular electron transfer. . Biochemistry . 44 . 42 . 13734–43 . 2005 . 16229463 . 10.1021/bi050907f .
• Tan WH, Eichler FS, Hoda S, etal . Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. . Pediatrics . 116 . 3 . 757–66 . 2005 . 16140720 . 10.1542/peds.2004-1897 . 6506338 .
• Astashkin AV, Johnson-Winters K, Klein EL, etal . Structural studies of the molybdenum center of the pathogenic R160Q mutant of human sulfite oxidase by pulsed EPR spectroscopy and 17O and 33S labeling. . J. Am. Chem. Soc. . 130 . 26 . 8471–80 . 2008 . 18529001 . 10.1021/ja801406f . 2779766 .
• Dronov R, Kurth DG, Möhwald H, etal . Layer-by-layer arrangement by protein-protein interaction of sulfite oxidase and cytochrome c catalyzing oxidation of sulfite. . J. Am. Chem. Soc. . 130 . 4 . 1122–3 . 2008 . 18177044 . 10.1021/ja0768690 .
• Edwards MC, Johnson JL, Marriage B, etal . Isolated sulfite oxidase deficiency: review of two cases in one family. . Ophthalmology . 106 . 10 . 1957–61 . 1999 . 10519592 . 10.1016/S0161-6420(99)90408-6 .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Rudolph MJ, Johnson JL, Rajagopalan KV, Kisker C . The 1.2 A structure of the human sulfite oxidase cytochrome b(5) domain. . Acta Crystallogr. D . 59 . Pt 7 . 1183–91 . 2003 . 12832761 . 10.1107/S0907444903009934 .
• Feng C, Wilson HL, Hurley JK, etal . Role of conserved tyrosine 343 in intramolecular electron transfer in human sulfite oxidase. . J. Biol. Chem. . 278 . 5 . 2913–20 . 2003 . 12424234 . 10.1074/jbc.M210374200 . free .
• Neumann M, Leimkühler S . Heavy metal ions inhibit molybdoenzyme activity by binding to the dithiolene moiety of molybdopterin in Escherichia coli. . FEBS J. . 275 . 22 . 5678–89 . 2008 . 18959753 . 10.1111/j.1742-4658.2008.06694.x . 45452761 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2002 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Wilson HL, Rajagopalan KV . The role of tyrosine 343 in substrate binding and catalysis by human sulfite oxidase. . J. Biol. Chem. . 279 . 15 . 15105–13 . 2004 . 14729666 . 10.1074/jbc.M314288200 . free .
• Hakonarson H, Qu HQ, Bradfield JP, etal . A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. . Diabetes . 57 . 4 . 1143–6 . 2008 . 18198356 . 10.2337/db07-1305 . free .

External links

• • Research Activity of Sarkar Group
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Sulfite oxidase, mitochondrial

Notes and References

1. D'Errico G, Di Salle A, La Cara F, Rossi M, Cannio R . Identification and characterization of a novel bacterial sulfite oxidase with no heme binding domain from Deinococcus radiodurans . J. Bacteriol. . 188 . 2 . 694–701 . January 2006 . 16385059 . 1347283 . 10.1128/JB.188.2.694-701.2006 .
2. Tan WH, Eichler FS, Hoda S, Lee MS, Baris H, Hanley CA, Grant PE, Krishnamoorthy KS, Shih VE . Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature . Pediatrics . 116 . 3 . 757–66 . September 2005 . 16140720 . 10.1542/peds.2004-1897 . 6506338 .
3. Cohen HJ, Betcher-Lange S, Kessler DL, Rajagopalan KV . Hepatic sulfite oxidase. Congruency in mitochondria of prosthetic groups and activity . J. Biol. Chem. . 247 . 23 . 7759–66 . December 1972 . 10.1016/S0021-9258(19)44588-2 . 4344230 . free .
4. Karakas E, Kisker C . Structural analysis of missense mutations causing isolated sulfite oxidase deficiency . . 21 . 3459–63 . November 2005 . 16234925 . 10.1039/b505789m .
5. Wilson HL, Wilkinson SR, Rajagopalan KV . The G473D mutation impairs dimerization and catalysis in human sulfite oxidase . Biochemistry . 45 . 7 . 2149–60 . February 2006 . 16475804 . 10.1021/bi051609l .
6. Feng C, Tollin G, Enemark JH . Sulfite oxidizing enzymes . Biochim. Biophys. Acta . 1774 . 5 . 527–39 . May 2007 . 17459792 . 1993547 . 10.1016/j.bbapap.2007.03.006 .