Affinage

CYP4F22

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

Length
531 aa
Mass
62.0 kDa
Annotated
2026-06-09
12 papers in source corpus 2 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP4F22 is an endoplasmic reticulum-resident cytochrome P450 that catalyzes the ω-hydroxylation of ultra-long-chain fatty acids (preferred substrate ≥C28), a step required for acylceramide production and skin permeability barrier formation (PMID:26056268). It is a type I membrane protein anchored in the ER, positioning ω-hydroxylation of ultra-long-chain fatty acids on the cytoplasmic face of the ER membrane (PMID:26056268). Ichthyosis-associated missense mutations directly reduce ω-hydroxylase activity, correlating enzymatic loss with the drastic depletion of acylceramide observed in patient skin and establishing CYP4F22 deficiency as a cause of autosomal recessive congenital ichthyosis (PMID:26056268). Certain pathogenic mutations (p.R282W, p.R397C) destabilize the protein, and mutant protein levels are partially restored by the HDAC inhibitor trichostatin A, implicating deacetylation-dependent regulation in mutant protein stability (PMID:35014717). Beyond these findings, the structural basis of substrate recognition and the regulatory mechanism linking acetylation to CYP4F22 stability have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2015 High

    Established the enzymatic identity and physiological role of CYP4F22 by showing it is an ω-hydroxylase selective for ultra-long-chain fatty acids (≥C28) required for skin acylceramide synthesis, resolving why its loss disrupts the epidermal barrier.

    Evidence In vitro enzyme activity assays of wild-type and ichthyosis-mutant proteins plus lipid analysis of patient skin

    PMID:26056268

    Open questions at the time
    • No structural model of substrate binding or chain-length selectivity
    • Cofactor/redox partner requirements not defined
    • Full in vivo reconstitution of the acylceramide pathway not demonstrated
  2. 2015 Medium

    Defined the subcellular site of catalysis by localizing CYP4F22 as a type I ER membrane protein, placing ultra-long-chain fatty acid ω-hydroxylation on the cytoplasmic side of the ER.

    Evidence Subcellular fractionation and membrane topology determination

    PMID:26056268

    Open questions at the time
    • Topology inferred from a single study
    • Spatial coupling to downstream acylceramide enzymes not mapped
  3. 2015 High

    Linked CYP4F22 dysfunction to disease by demonstrating that ichthyosis-associated missense mutations reduce ω-hydroxylase activity, establishing a direct genotype–enzyme–phenotype chain for autosomal recessive congenital ichthyosis.

    Evidence Comparative in vitro enzyme activity assays of wild-type vs. multiple disease-associated mutant proteins with patient lipid correlation

    PMID:26056268

    Open questions at the time
    • Does not address mutations acting via protein stability rather than catalysis
    • Variant-specific severity not systematically resolved
  4. 2022 Medium

    Revealed a stability-based mechanism of pathogenicity by showing that p.R282W and p.R397C reduce CYP4F22 protein levels and are rescued by HDAC inhibition, implicating deacetylation factors in mutant protein turnover.

    Evidence In vitro protein quantification with trichostatin A (HDAC inhibitor) rescue

    PMID:35014717

    Open questions at the time
    • Mechanism of deacetylation-mediated regulation not elucidated
    • Single-lab in vitro study without endogenous validation
    • Acetylation site(s) and responsible enzymes unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYP4F22 recognizes ultra-long-chain substrates structurally and how acetylation/deacetylation controls its stability and activity remain unresolved.
  • No crystal or cryo-EM structure
  • Redox partner and electron-transfer requirements undefined
  • Direct acetylation of CYP4F22 not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0016787 hydrolase activity 1
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 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 with a preferred substrate of fatty acids with carbon chain length ≥C28, and is required for acylceramide production in skin. In vitro enzyme activity assay with ichthyosis-mutant proteins showing reduced activity; lipid analysis of patient skin showing drastic decrease in acylceramide Proceedings of the National Academy of Sciences of the United States of America High 26056268
2015 CYP4F22 is a type I membrane protein that localizes 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 membrane topology determination (direct localization experiment) Proceedings of the National Academy of Sciences of the United States of America Medium 26056268
2015 Ichthyosis-associated missense mutations in CYP4F22 result in reduced ω-hydroxylase enzyme activity, demonstrating a direct correlation between enzymatic activity loss and disease pathology. In vitro enzyme activity assay of wild-type vs. ichthyosis-mutant CYP4F22 proteins Proceedings of the National Academy of Sciences of the United States of America High 26056268
2022 Two pathogenic missense mutations (p.R282W and p.R397C) in CYP4F22 significantly reduce the amount of CYP4F22 protein in vitro, and this reduction can be rescued by trichostatin A (TSA) treatment, implicating deacetylation factors in regulating mutant CYP4F22 protein stability. In vitro functional studies measuring mutant CYP4F22 protein levels; TSA (HDAC inhibitor) rescue experiment The Journal of dermatology Medium 35014717

Source papers

Stage 0 corpus · 12 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 138 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
2026 Identification of Pathogenic Variants in CYP4F22, FLG, ALOX12B, and NIPAL4 in a Case Series of Inherited Ichthyosis. International journal of molecular sciences 0 42196615
2024 Autosomal recessive congenital ichthyosis due to novel CYP4F22 mutation presenting with a collodion membrane and ocular manifestations. Pediatric dermatology 0 38196085

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