Phytanoyl-CoA dioxygenase explained

In enzymology, a phytanoyl-CoA dioxygenase is an enzyme that catalyzes the chemical reaction

phytanoyl-CoA + 2-oxoglutarate + O₂

2-hydroxyphytanoyl-CoA + succinate + CO₂

The three substrates of this enzyme are phytanoyl-CoA, 2-oxoglutarate (2OG), and O₂, whereas its three products are 2-hydroxyphytanoyl-CoA, succinate, and CO₂.

This enzyme belongs to the family of iron(II)-dependent oxygenases, which typically incorporate one atom of dioxygen into the substrate and one atom into the succinate carboxylate group. The mechanism is complex, but is believed to involve ordered binding of 2-oxoglutarate to the iron(II) containing enzyme followed by substrate. Binding of substrate causes displacement of a water molecule from the iron(II) cofactor, leaving a vacant coordination position to which dioxygen binds. A rearrangement occurs to form a high energy iron-oxygen species (which is generally thought to be an iron(IV)=O species) that performs the actual oxidation reaction.^{[1] [2]}

Nomenclature

The systematic name of this enzyme class is phytanoyl-CoA, 2-oxoglutarate:oxygen oxidoreductase (2-hydroxylating). These enzymes are also called phytanoyl-CoA hydroxylases and phytanoyl-CoA alpha-hydroxylases.^[3]

Examples

In humans, phytanoyl-CoA hydroxylase is encoded by the PHYH (aka PAHX) gene and is required for the alpha-oxidation of branched chain fatty acids (e.g. phytanic acid) in peroxisomes. PHYH deficiency results in the accumulation of large tissue stores of phytanic acid and is the major cause of Refsum disease.^[4]

Related enzymes

Iron(II) and 2OG-dependent oxygenases are common in microorganisms, plants, and animals; the human genome is predicted to contain about 80 examples, and the model plant Arabidopsis thaliana likely contains more. In plants and microorganisms this enzyme family is associated with a large diversity of oxidative reactions.^[5]

Further reading

• Jansen GA, Mihalik SJ, Watkins PA, Jakobs C, Moser HW, Wanders RJ . Characterization of phytanoyl-Coenzyme A hydroxylase in human liver and activity measurements in patients with peroxisomal disorders . Clinica Chimica Acta; International Journal of Clinical Chemistry . 271 . 2 . 203–11 . Mar 1998 . 9565335 . 10.1016/S0009-8981(97)00259-3 . free .
• Jansen GA, Mihalik SJ, Watkins PA, Moser HW, Jakobs C, Denis S, Wanders RJ . Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome: direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans . Biochemical and Biophysical Research Communications . 229 . 1 . 205–10 . Dec 1996 . 8954107 . 10.1006/bbrc.1996.1781 . free .
• Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muijsers AO, Skjeldal OH, Stokke O, Jakobs C, Besley GT, Wraith JE, Wanders RJ . Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene . Nature Genetics . 17 . 2 . 190–3 . Oct 1997 . 9326940 . 10.1038/ng1097-190 . 5856245 .
• Mihalik SJ, Rainville AM, Watkins PA . Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alpha-hydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors . European Journal of Biochemistry . 232 . 2 . 545–51 . Sep 1995 . 7556205 . 10.1111/j.1432-1033.1995.545zz.x . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Refsum Disease

Notes and References

1. Book: Hausinger. Robert P. . 2-Oxoglutarate-Dependent Oxygenases . 2015. 1–58. 10.1039/9781782621959-00001. CHAPTER 1. Biochemical Diversity of 2-Oxoglutarate-Dependent Oxygenases . Metallobiology . 978-1-84973-950-4 . 85596364 .
2. Martinez S, Hausinger RP . Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases . The Journal of Biological Chemistry . 290 . 34 . 20702–11 . Aug 2015 . 26152721 . 10.1074/jbc.R115.648691 . 4543632. free .
3. Web site: PHYH phytanoyl-CoA 2-hydroxylase [Homo sapiens (human) ]]. National Center for Biotechnology Information.
4. Mihalik SJ, Morrell JC, Kim D, Sacksteder KA, Watkins PA, Gould SJ . Identification of PAHX, a Refsum disease gene . Nature Genetics . 17 . 2 . 185–9 . Oct 1997 . 9326939 . 10.1038/ng1097-185 . 39214017 .
5. McDonough MA, Loenarz C, Chowdhury R, Clifton IJ, Schofield CJ . Structural studies on human 2-oxoglutarate dependent oxygenases . Current Opinion in Structural Biology . 20 . 6 . 659–72 . Dec 2010 . 20888218 . 10.1016/j.sbi.2010.08.006 .