Carnitine transport and fatty acid oxidation.

Genetic polymorphisms in VKORC1 and CYP2C9, genes controlling vitamin K1 (VK1) epoxide reduction and (S)-warfarin metabolism, respectively, are major contributors to interindividual variability in warfarin dose. The V433M polymorphism (rs2108622) in CYP4F2 has also been associated with warfarin dose and speculatively linked to altered VK1 metabolism. Therefore, the purpose of the present study was to determine the role of CYP4F2 and the V433M polymorphism in the metabolism of VK1 by human liver. In vitro metabolic experiments with accompanying liquid chromatography-tandem mass spectrometry analysis demonstrated that recombinant CYP4F2 (Supersomes) and human liver microsomes supplemented with NADPH converted VK1 to a single product. A screen of all commercially available P450 Supersomes showed that only CYP4F2 was capable of metabolizing VK1 to this product. Steady-state kinetic analysis with recombinant CYP4F2 and with human liver microsomes revealed a substrate Km of 8 to 10 μM. Moreover, anti-CYP4F2 IgG, as well as several CYP4F2-selective chemical inhibitors, substantially attenuated the microsomal reaction. Finally, human liver microsomes genotyped for rs2108622 demonstrated reduced vitamin K1 oxidation and lower CYP4F2 protein concentrations in carriers of the 433M minor allele. These data demonstrate that CYP4F2 is a vitamin K1 oxidase and that carriers of the CYP4F2 V433M allele have a reduced capacity to metabolize VK1, secondary to an rs2108622-dependent decrease in steady-state hepatic concentrations of the enzyme. Therefore, patients with the rs2108622 polymorphism are likely to have elevated hepatic levels of VK1, necessitating a higher warfarin dose to elicit the same anticoagulant response.

https://sop.washington.edu/wp-content/uploads/Publication_Rieder_Rettie.pdf

Cyp4f2 is a vitamin k1 oxidase: an explanation for altered warfarin dose in carriers of the v433m variant

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

Fatty acids (FAs) can be degraded via different mechanisms including α-, β- and ω-oxidation In humans, a range of different genetic diseases has been identified in which either mitochondrial FA β-oxidation, peroxisomal FA β-oxidation or FA α-oxidation is impaired Treatment options for most of these disorders are limited This has prompted us to study FA ω-oxidation as a rescue pathway for these disorders, based on the notion that if the ω-oxidation of specific FAs could be upregulated one could reduce the accumulation of these FAs and the subsequent detrimental effects in the different groups of disorders In this minireview, we describe our current state of knowledge in this area with special emphasis on Refsum disease and X-linked adrenoleukodystrophy

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2010.07947.x

Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans.

X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history

Very-long-chain fatty acids (VLCFAs) have long been known to be degraded exclusively in peroxisomes via beta-oxidation. A defect in peroxisomal beta-oxidation results in elevated levels of VLCFAs and is associated with the most frequent inherited disorder of the central nervous system white matter, X-linked adrenoleukodystrophy. Recently, we demonstrated that VLCFAs can also undergo omega-oxidation, which may provide an alternative route for the breakdown of VLCFAs. The omega-oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce omega-hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from omega-hydroxy-VLCFAs. We demonstrate that very-long-chain dicarboxylic acids are produced via two independent pathways. The first is mediated by an as yet unidentified, microsomal NAD(+)-dependent alcohol dehydrogenase and fatty aldehyde dehydrogenase, which is encoded by the ALDH3A2 gene and is deficient in patients with Sjogren-Larsson syndrome. The second pathway involves the NADPH-dependent hydroxylation of omega-hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of omega-hydroxy-VLCFAs occurs predominantly via the NAD(+)-dependent route. Overall, our data demonstrate that in humans all enzymes are present for the complete conversion of VLCFAs to their corresponding very-long-chain dicarboxylic acids.

/pdf/characterization-of-the-human-omega-oxidation-pathway-for-2r5xg204f9.pdf

Robert-Jan Sanders

Papers

Characterization of the human {omega}-oxidation pathway for {omega}-hydroxy-very-long-chain fatty acids