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Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>\n                    Heme is an essential prosthetic group involved in multiple biological processes in nearly all organisms. Heme biosynthesis is initiated by the pyridoxal 5\u2032-phosphate\u2013dependent enzyme aminolevulinic acid synthase (ALAS). Mutations in ALAS cause multiple hematological diseases. Despite sharing approximately 70% sequence similarity, ALAS homologs exhibit distinct expression and regulatory mechanisms. However, the molecular basis for their functional divergence remains poorly understood. Here, we used x-ray crystallography and molecular dynamics simulations to elucidate the structure and dynamics of\n                    <jats:italic toggle=\"yes\">Saccharomyces cerevisiae<\/jats:italic>\n                    ALAS (scALAS) upon substrate binding. We identified critical conformational changes that occur during catalysis, regulating enzyme activity and protein-protein interactions specific to eukaryotic heme synthesis. Using evolution-guided engineering, we generated scALAS variants with altered catalytic activity and cellular metabolic profiles. Our findings reveal molecular and structural mechanisms underlying heme synthesis regulation and establish a framework for developing targeted therapeutics to treat heme-deficiency disorders and inform a rational design of next-generation therapeutic tools.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aef7768","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:58:53Z","timestamp":1792173533000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0041-5700","authenticated-orcid":true,"given":"Jenny U.","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 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