CYP4 Isoform Specificity in the ω-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease

Abstract

The saturated C20 isoprenoid phytanic acid is physiologically derived from phytol released in the degradation of chlorophyll. The presence of a C-3 methyl group in this substrate blocks normal ␤-oxidation, so phytanic acid degradation primarily occurs by initial peroxisomal ␣-oxidation to shift the register of the methyl group. However, individuals with Refsum's disease are genetically deficient in the required phytanoyl-CoA ␣-hydroxylase and suffer from neurological pathologies caused by the accumulation of phytanic acid. Recent work has shown that phytanic acid can also be catabolized by a pathway initiated by -hydroxylation of the hydrocarbon chain, followed by oxidation of the alcohol to the acid and conventional ␤-oxidation. However, the enzymes responsible for the -hydroxylation of phytanic acid have not been identified. In this study, we have determined the activities of all of the rat and human CYP4A enzymes and two of the rat CYP4F enzymes, with respect to the -hydroxylation of phytanic acid. Furthermore, we have shown that the ability to -hydroxylate phytanic acid is elevated in microsomes from rats pretreated with clofibrate. The results support a possible role for CYP4 enzyme elevation in the elimination of phytanic acid in Refsum's disease patients.

Biochemical and structural characterization of CYP124: A methyl-branched lipid ω-hydroxylase from Mycobacterium tuberculosis

“…deriving energy from carbon sources with methyl branching (35,36). In mammals, -oxidation of branched lipids, such as phytanic acid, shifts the register of the ␤-substituted carbon chain so that ␤-oxidation can occur (23). CYP124 could conceivably function in oxidative degradation or balancing of Mtb lipid and carbon pools.…”

Omega oxidation of 3-hydroxy fatty acids by the human CYP4F gene subfamily enzyme CYP4F11

“…4 Although laurate, an exemplary fatty acid P450 substrate, is extensively metabolized by CYP4F11 (Table 1), its 3-hydroxylated analog is not, indicating that chain length may be one determinant governing 3-OHFA v-hydroxylation by CYP4F11. Analogous to other CYP4F enzymes (3,4,34), CYP4F11 exhibited complete regioselectivity for the 3-OHFA vterminal carbon and did not oxidize these substrates at the adjacent v-1 position. In fact, the lack of conversion of 3-hydroxystearate and 3-hydroxypalmitate to their v-1 hydroxylated derivatives by native hepatic microsomes suggests that these 3-OHFAs are not substrates for CYP2E1, the principal fatty acid v-1 hydroxylating enzyme expressed in human liver (29,30,35,36).…”

CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant

“…The CYP4 family is known to -hydroxylate a wide variety of fatty acids, with the CYP4F subfamily showing preferential activity toward long-chain (C 16 -C 26 ) fatty acids (Sanders et al, 2006;Hardwick, 2008;Sanders et al, 2008). Furthermore, CYP4F2 is the primary human enzyme responsible for -hydroxylating a range of tocopherols (Sontag and Parker, 2007), whose various structures all consist of a cyclized head group attached to a side chain of three linear isoprenyl units (similar to VK1), as well as phytanic acid, which is essentially the side chain of VK1 lacking the menadione head group (Xu et al, 2006). VK1, with its mostly saturated (C 20 ) phytyl side chain composed of four linearly conjoined isoprenyl units is, therefore, a prime candidate to undergo CYP4F2-mediated -hydroxylation.…”