Affinage

CYP4F22

Ultra-long-chain fatty acid omega-hydroxylase · UniProt Q6NT55

Length
531 aa
Mass
62.0 kDa
Annotated
2026-04-28
11 papers in source corpus 2 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP4F22 is a type I endoplasmic reticulum membrane protein that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase, catalyzing the production of ω-hydroxylated fatty acid precursors essential for acylceramide biosynthesis and skin permeability barrier formation (PMID:26056268). The enzyme's active site faces the cytoplasmic side of the ER, and ichthyosis-causing mutations directly reduce its ω-hydroxylase activity, establishing a genotype–phenotype link between loss of catalytic function, acylceramide deficiency, and autosomal recessive congenital ichthyosis (PMID:26056268). Pathogenic missense variants (e.g., p.R282W, p.R397C) also destabilize the protein, and this instability can be rescued by trichostatin A, implicating deacetylation-dependent mechanisms in CYP4F22 protein turnover (PMID:35014717).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2015 High

    Resolving the long-standing question of which enzyme performs ω-hydroxylation in the acylceramide pathway, this work demonstrated that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase with preference for ≥C28 substrates, localized as a type I ER membrane protein with its catalytic face in the cytoplasm, and that ichthyosis-causing mutations directly reduce this activity — thereby linking enzymatic function, subcellular topology, and disease causation in a single framework.

    Evidence In vitro enzyme activity assays with varying chain-length fatty acids, subcellular fractionation/ER localization, lipid analysis of ichthyosis patient samples, and functional testing of disease-associated mutant proteins

    PMID:26056268

    Open questions at the time
    • No crystal or cryo-EM structure of CYP4F22 to explain substrate chain-length selectivity
    • The electron-donor partner (cytochrome P450 reductase or other) and its interaction interface are not characterized
    • Whether CYP4F22 also hydroxylates non-fatty-acid substrates has not been tested
  2. 2022 Medium

    Beyond catalytic loss, pathogenic CYP4F22 missense mutations were shown to reduce protein stability, and rescue by the deacetylase inhibitor trichostatin A implicated acetylation/deacetylation balance as a post-translational regulatory mechanism governing CYP4F22 turnover.

    Evidence In vitro expression of p.R282W and p.R397C mutant proteins with quantification of protein levels ± TSA treatment

    PMID:35014717

    Open questions at the time
    • The specific lysine residue(s) whose acetylation state controls CYP4F22 stability have not been identified
    • Whether TSA acts directly on CYP4F22 acetylation or indirectly through chaperone or proteasomal pathways is unresolved
    • Rescue of enzyme activity (not just protein level) by TSA was not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CYP4F22's ultra-long-chain substrate selectivity, the identity of its redox partner(s), whether pharmacological stabilization of mutant protein can restore barrier function in vivo, and the full spectrum of post-translational modifications regulating its activity and turnover.
  • No in vivo animal model recapitulating CYP4F22-dependent ichthyosis with functional rescue
  • Structural model for substrate binding and chain-length selectivity is absent
  • Relationship between CYP4F22 and other acylceramide pathway enzymes (e.g., PNPLA1, CERS3) at the protein complex level is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 1 R-HSA-1643685 Disease 1

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase that preferentially hydroxylates fatty acids with carbon chain lengths of ≥C28, producing the ω-hydroxylated fatty acid precursor required for acylceramide biosynthesis and skin permeability barrier formation. Enzyme activity assays with fatty acid substrates of varying chain lengths; lipid analysis of ichthyosis patient samples showing drastic decrease in acylceramide; ichthyosis-associated mutant proteins showing reduced enzyme activity Proceedings of the National Academy of Sciences of the United States of America High 26056268
2015 CYP4F22 is a type I membrane protein localized to the endoplasmic reticulum (ER), indicating that ω-hydroxylation of ultra-long-chain fatty acids occurs on the cytoplasmic side of the ER. Subcellular fractionation and localization experiments establishing ER membrane topology Proceedings of the National Academy of Sciences of the United States of America High 26056268
2015 Ichthyosis-causing mutations in CYP4F22 reduce enzyme ω-hydroxylase activity, establishing a direct genotype-phenotype correlation between loss of catalytic function and acylceramide deficiency. Enzyme activity assays on ichthyosis-mutant CYP4F22 proteins combined with lipid analysis of patient-derived samples Proceedings of the National Academy of Sciences of the United States of America High 26056268
2022 Two pathogenic CYP4F22 missense mutations (p.R282W and p.R397C) significantly reduce CYP4F22 protein levels, and this reduction can be rescued by treatment with the deacetylase inhibitor trichostatin A (TSA), implicating deacetylation-dependent protein stability regulation. In vitro functional study with mutant protein expression; TSA treatment rescue experiment The Journal of dermatology Medium 35014717

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. Proceedings of the National Academy of Sciences of the United States of America 136 26056268
2011 Finding homes for orphan cytochrome P450s: CYP4V2 and CYP4F22 in disease states. Molecular interventions 44 21540472
2018 Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis. Human mutation 24 30011118
2015 Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby. Pediatric dermatology 15 26646773
2020 Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation. PloS one 13 32069299
2017 Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations. The British journal of dermatology 10 27449533
2019 A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene. International journal of dermatology 6 31020658
2022 CYP4F22-Related Autosomal Recessive Congenital Ichthyosis: Clinical Presentation. Cureus 3 35350521
2021 Novel compound heterozygous mutations in the CYP4F22 gene in a patient with autosomal recessive congenital ichthyosis. Clinical case reports 3 34917360
2022 Whole-exome sequencing identified a novel pathogenic mutation of the CYP4F22 gene in a Chinese patient with autosomal recessive congenital ichthyosis and in vitro study of the mutant CYP4F22 protein. The Journal of dermatology 2 35014717
2024 Autosomal recessive congenital ichthyosis due to novel CYP4F22 mutation presenting with a collodion membrane and ocular manifestations. Pediatric dermatology 0 38196085