Heme-dependent Inactivation of 5-Aminolevulinate Synthase from Caulobacter crescentus

Scientific Reports
Hiroko IkushiroTakato Yano

Abstract

The biosynthesis of heme is strictly regulated, probably because of the toxic effects of excess heme and its biosynthetic precursors. In many organisms, heme biosynthesis starts with the production of 5-aminolevulinic acid (ALA) from glycine and succinyl-coenzyme A, a process catalyzed by a homodimeric enzyme, pyridoxal 5'-phosphate (PLP)-dependent 5-aminolevulinate synthase (ALAS). ALAS activity is negatively regulated by heme in various ways, such as the repression of ALAS gene expression, degradation of ALAS mRNA, and inhibition of mitochondrial translocation of the mammalian precursor protein. There has been no clear evidence, however, that heme directly binds to ALAS to negatively regulate its activity. We found that recombinant ALAS from Caulobacter crescentus was inactivated via a heme-mediated feedback manner, in which the essential coenzyme PLP was rel eased to form the inactive heme-bound enzyme. The spectroscopic properties of the heme-bound ALAS showed that a histidine-thiolate hexa-coordinated ferric heme bound to each subunit with a one-to-one stoichiometry. His340 and Cys398 were identified as the axial ligands of heme, and mutant ALASs lacking either of these ligands became resistant to heme-mediated inhibition....Continue Reading

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Citations

Jun 13, 2020·The FEBS Journal·Joachim KloehnDominique Soldati-Favre
Sep 25, 2020·Nature Communications·Clare R HardingSebastian Lourido
Nov 22, 2019·Chemical Society Reviews·Toru ShimizuMarkéta Martínková
Jul 3, 2021·International Journal of Molecular Sciences·Jitka RichtováMiroslav Oborník
Sep 15, 2021·Critical Reviews in Biochemistry and Molecular Biology·Angela S FleischhackerStephen W Ragsdale

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Methods Mentioned

BETA
Thin-layer chromatography
Thermal
circular dichroism
electron paramagnetic resonance
X-ray
column
Protein Liquid Chromatography
NMR
Protein Assay
electrophoresis

Software Mentioned

Genetyx
cALAS

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