ArticleNucleic acids research2022
Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 69 citations in OpenAlex.
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- Design and Biological Evaluation of ALKBH2 and ALKBH5 Inhibitors as Adjuvants to Temozolomide-Based Glioblastoma Treatment.Biology · 2026Article
- The Role of NMedComm · 2026Review
- FTO separation-of-function mutations alter mbioRxiv : the preprint server for biology · 2026Article
- N6-methyladenosine (m6A) methylation in adipose tissue: role, regulation, and therapeutic potential.Cellular and molecular life sciences : CMLS · 2026Review
- The N6-Methyladenosine RNA Demethylase AlkB Homolog 5 (ALKBH5) in Metabolic Diseases: Molecular Mechanisms and Pharmacological Implications-A Review.Biomolecules · 2026Review
- A distinct subclade of AlkB family demethylases in ciliates safeguards the positional fidelity of eukaryotic NProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Spatiotemporal dynamics of radioresistance: decoding macrophage-driven radioprotective niches through temporal-spatial reprogramming.Molecular cancer · 2026Review
- Regulation of RNA-binding proteins by small biomolecules.Nature reviews. Molecular cell biology · 2026Review
- Epitranscriptomic modifications in embryonic development: insights into natural and ART-induced mechanisms and implications.Human reproduction update · 2026Review
- Emerging Dual Roles of ALKBH5 in Ischemia-reperfusion Injury: Mechanisms and Therapeutic Implications.Cell biochemistry and biophysics · 2026Review
- Identification of immune-related targets of N6-methyladenosine regulators in hepatocellular carcinoma via RNA-seq analysis.Translational cancer research · 2026Article
- NBiomolecules · 2026Review
- Context-dependent functions of ALKBH5: a mechanistic framework linking cellular stress responses, immune regulation, viral infection, and therapeutic vulnerabilities.Frontiers in immunology · 2026Review
- ALKBH5 induces macrophage activation to promote renal fibrosis via Retnla.Renal failure · 2025Article
- Evidence human FTO catalyses hydroxylation of N6-methyladenosine without direct formation of a demethylated product contrasting with ALKBH5/2/3 and bacterial AlkB.Nucleic acids research · 2025Article
- Revealing the catalytic mechanism of the Fe(II)/2-oxoglutarate-dependent human epigenetic modifying enzyme ALKBH5.Cell reports. Physical science · 2025Article
- Dynamic Rendition of Adipose Genes Under Epigenetic Regulation: Revealing New Mechanisms of Obesity Occurrence.Current issues in molecular biology · 2025Review
- ALKBH5 regulates intrauterine adhesion progression through m6A dependent FABP4 mRNA stabilization and serum lipid metabolism.Communications biology · 2025Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
AlkB homologue 5 (ALKBH5) is a ferrous iron and 2-oxoglutarate dependent oxygenase that demethylates RNA N6-methyladenosine (m6A), a post-transcriptional RNA modification with an emerging set of regulatory roles. Along with the fat mass and obesity-associated protein (FTO), ALKBH5 is one of only two identified human m6A RNA oxidizing enzymes and is a potential target for cancer treatment. Unlike FTO, ALKBH5 efficiently catalyzes fragmentation of its proposed nascent hemiaminal intermediate to give formaldehyde and a demethylated nucleoside. A detailed analysis of the molecular mechanisms used by ALKBH5 for substrate recognition and m6A demethylation is lacking. We report three crystal structures of ALKBH5 in complex with an m6A-ssRNA 8-mer substrate and supporting biochemical analyses. Strikingly, the single-stranded RNA substrate binds to the active site of ALKBH5 in a 5'-3' orientation that is opposite to single-stranded or double-stranded DNA substrates observed for other AlkB subfamily members, including single-stranded DNA bound to FTO. The combined structural and biochemical results provide insight into the preference of ALKBH5 for substrates containing a (A/G)m6AC consensus sequence motif. The results support a mechanism involving formation of an m6A hemiaminal intermediate, followed by efficient ALKBH5 catalyzed demethylation, enabled by a proton shuttle network involving Lys132 and Tyr139.
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