Phytol and phytanic acid are minor constituents of the human diet. Phytol is known to be converted to phytanic acid in human. The pathway of degradation of phytanic acid has been established by Steinberg and coworkers. Phytanic acid first undergoes Alpha-oxidation to produce pristanic acid and CO2; pristanic acid is then degraded via Beta-oxidation. In patients with Refsum's disease, an inherited disorder of the nervous system, phytanic acid accumulates is blood and tissues due to defective degradation. The enzymatic defect in patients has been localized to the initial Alpha-hydroxylation step. The objective is to elucidate the individual steps in the metabolism of phytol and phytanic acid in rat liver and human skin fibroblasts. Since Alpha-hydroxylation may be the rate limiting step of Alpha-oxidation and has been implicated in Refsum's disease, development of an Alpha-hydroxylation assay and elucidation of this step are important to understand the mechanism of Refsum's disease. Since phytol is inevitably consumed by human understanding its metabolism is important. Further understanding the metabolism of phytol may lead to a general understanding of long chain alcohol oxidation. Specifically it is proposed to (1) purify and elucidate the mechanism of phytol-phytanate conversion (2) continue studies on phytanic acid Alpha-oxidation and Alpha-hydroxylation (3) evaluate role of peroxisomes in pristanate Beta-oxidation (4) develop potential irreverisble inhibitors that might inhibit phytanic acid Alpha-oxidase in vivo and permit development of an animal model for Refsum's disease (5) evaluate phytol and phytanic acid metabolism in other peroxisomal diseases and (6) search for lipases that hydrolyze mono- and diphytanyl triglyceride and determine the position of attachment to glycerol in diphytanyl triglyceride that accumulates in patients. (2-3H)Phytanic acid will be synthesized and use of this might provide a convenient and simple assay for Alpha-hydroxylation which will be of immense help in screening for deficient Alpha-hydroxylase in patients. The studies proposed may elucidate for the first time the precise subcellular localization of enzymes of phytol and phytanic acid metabolism.
| Muralidharan, F N; Muralidharan, V B (1987) Phytanic acid alpha oxidation in rat liver: studies on alpha hydroxylation. Int J Biochem 19:663-70 |
