ArticleMolecular medicine (Cambridge, Mass.)2013
Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria.
Article in Molecular medicine (Cambridge, Mass.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 42 citations in OpenAlex.
- Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.Science advances · 2026Article
- Milestones in the Elucidation of Heme Biosynthesis.Chemical reviews · 2026Review
- An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.Science (New York, N.Y.) · 2026Article
- Identification of a novel nonsense mutation and a recurrent missense mutation in UROS gene in a patient with congenital erythropoietic porphyria.Frontiers in genetics · 2025Article
- Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of theFrontiers in medicine · 2024Article
- Protoporphyrin IX-induced phototoxicity: Mechanisms and therapeutics.Pharmacology & therapeutics · 2023Review
- The yeast ALA synthase C-terminus positively controls enzyme structure and function.Protein science : a publication of the Protein Society · 2023Article
- New Avenues of Heme Synthesis Regulation.International journal of molecular sciences · 2022Review
- ABCB6 polymorphisms are not overly represented in patients with porphyria.Blood advances · 2022Article
- Structural Basis for Allostery in PLP-dependent Enzymes.Frontiers in molecular biosciences · 2022Review
- An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms.Frontiers in molecular biosciences · 2022Review
- The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors.Blood advances · 2021Article
- SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature.Human mutation · 2021Review
- Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria.Bioscience reports · 2021Article
- Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release.Nature communications · 2020Article
- Strong correlation of ferrochelatase enzymatic activity with Mitoferrin-1 mRNA in lymphoblasts of patients with protoporphyria.Molecular genetics and metabolism · 2019Article
- Congenital erythropoietic porphyria: Recent advances.Molecular genetics and metabolism · 2019Review
- Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes.Molecular genetics and metabolism · 2019Review
- Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants.Molecular medicine (Cambridge, Mass.) · 2019Article
- Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis.Blood · 2018Article
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4 authors at 2 institutions in 1 country.
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Abstract
X-linked protoporphyria (XLP) (MIM 300752) is a recently recognized erythropoietic porphyria due to gain-of-function mutations in the erythroid-specific aminolevulinate synthase gene (ALAS2). Previously, two exon 11 small deletions, c.1699_1670ΔAT (ΔAT) and c.1706_1709ΔAGTG (ΔAGTG), that prematurely truncated or elongated the ALAS2 polypeptide, were reported to increase enzymatic activity 20- to 40-fold, causing the erythroid accumulation of protoporphyrins, cutaneous photosensitivity and liver disease. The mutant ΔAT and ΔAGTG ALAS2 enzymes, two novel mutations, c.1734ΔG (ΔG) and c.1642C>T (p.Q548X), and an engineered deletion c.1670-1671TC>GA p.F557X were expressed, and their purified enzymes were characterized. Wild-type and ΔAGTG enzymes exhibited similar amounts of 54- and 52-kDa polypeptides on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whereas the ΔAT and p.F557X had only 52-kDa polypeptides. Compared to the purified wild-type enzyme, ΔAT, ΔAGTG and Q548X enzymes had increased specific activities that were only 1.8-, 3.1- and 1.6-fold, respectively. Interestingly, binding studies demonstrated that the increased activity Q548X enzyme did not bind to succinyl-CoA synthetase. The elongated ΔG enzyme had wild-type specific activity, kinetics and thermostability; twice the wild-type purification yield (56 versus 25%); and was primarily a 54-kDa form, suggesting greater stability in vivo. On the basis of studies of mutant enzymes, the maximal gain-of function region spanned 57 amino acids between 533 and 580. Thus, these ALAS2 gain-of-function mutations increased the specific activity (ΔAT, ΔAGTG and p.Q548X) or stability (ΔG) of the enzyme, thereby leading to the increased erythroid protoporphyrin accumulation causing XLP.
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