ArticleThe Journal of biological chemistry2010
Targeting the active site gate to yield hyperactive variants of 5-aminolevulinate synthase.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.Science advances · 2026Article
- Growth-coupled selection of 5-aminolevulinic acid synthetase mutants for 5-aminolevulinic acid biosynthesis inFrontiers in microbiology · 2025Article
- The yeast ALA synthase C-terminus positively controls enzyme structure and function.Protein science : a publication of the Protein Society · 2023Article
- Systems metabolic engineering of Escherichia coli for hyper-production of 5‑aminolevulinic acid.Biotechnology for biofuels and bioproducts · 2023Article
- Structural Basis for Allostery in PLP-dependent Enzymes.Frontiers in molecular biosciences · 2022Review
- Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release.Nature communications · 2020Article
- 5-Aminolevulinate synthase catalysis: The catcher in heme biosynthesis.Molecular genetics and metabolism · 2019Review
- Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants.Molecular medicine (Cambridge, Mass.) · 2019Article
- Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase.International journal of molecular sciences · 2018Article
- Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme.Structure (London, England : 1993) · 2018Article
- Investigating the bifunctionality of cyclizing and "classical" 5-aminolevulinate synthases.Protein science : a publication of the Protein Society · 2018Article
- 5-Aminolevulinic acid production from inexpensive glucose by engineering the C4 pathway in Escherichia coli.Journal of industrial microbiology & biotechnology · 2017Article
- Asn-150 of Murine Erythroid 5-Aminolevulinate Synthase Modulates the Catalytic Balance between the Rates of the Reversible Reaction.The Journal of biological chemistry · 2015Article
- Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt the Conformational Equilibrium and Enhance Product Release.Biochemistry · 2015Article
- Catalytically active alkaline molten globular enzyme: Effect of pH and temperature on the structural integrity of 5-aminolevulinate synthase.Biochimica et biophysica acta · 2014Article
- Unstable reaction intermediates and hysteresis during the catalytic cycle of 5-aminolevulinate synthase: implications from using pseudo and alternate substrates and a promiscuous enzyme variant.The Journal of biological chemistry · 2014Article
- Expression of murine 5-aminolevulinate synthase variants causes protoporphyrin IX accumulation and light-induced mammalian cell death.PloS one · 2014Article
- Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria.Molecular medicine (Cambridge, Mass.) · 2013Article
- X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2).The Journal of biological chemistry · 2012Article
- Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis.Biochimica et biophysica acta · 2011Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The rate of porphyrin biosynthesis in mammals is controlled by the activity of the pyridoxal 5'-phosphate-dependent enzyme 5-aminolevulinate synthase (EC 2.3.1.37). Based on the postulate that turnover in this enzyme is controlled by conformational dynamics associated with a highly conserved active site loop, we constructed a variant library by targeting imperfectly conserved noncatalytic loop residues and examined the effects on product and porphyrin production. Functional loop variants of the enzyme were isolated via genetic complementation in Escherichia coli strain HU227. Colony porphyrin fluorescence varied widely when bacterial cells harboring the loop variants were grown on inductive media; this facilitated identification of clones encoding unusually active enzyme variants. Nine loop variants leading to high in vivo porphyrin production were purified and characterized kinetically. Steady state catalytic efficiencies for the two substrates were increased by up to 100-fold. Presteady state single turnover reaction data indicated that the second step of quinonoid intermediate decay, previously assigned as reaction rate-limiting, was specifically accelerated such that in three of the variants this step was no longer kinetically significant. Overall, our data support the postulate that the active site loop controls the rate of product and porphyrin production in vivo and suggest the possibility of an as yet undiscovered means of allosteric regulation.
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