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The combination of increasing antibiotic resistance in this pathogen and the lack of an efficacious vaccine underscores the importance of understanding how\n                    <jats:italic>S. aureus<\/jats:italic>\n                    maintains metabolic homeostasis in a variety of environments, particularly during infection. Within the host,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    must regulate cellular levels of the cofactor heme to support enzymatic activities without encountering heme toxicity.\n                    <jats:underline>G<\/jats:underline>\n                    lutamyl\n                    <jats:underline>tR<\/jats:underline>\n                    NA\n                    <jats:underline>r<\/jats:underline>\n                    eductase (GtrR), the enzyme catalyzing the first committed step in heme synthesis, is an important regulatory node of heme synthesis in Bacteria, Archaea, and Plantae. In many organisms, heme status negatively regulates the abundance of GtrR, controlling flux through the heme synthesis pathway. We identified two residues within GtrR, H32 and R214, that are important for GtrR-heme binding. However, in strains expressing either GtrR\n                    <jats:sup>H32A<\/jats:sup>\n                    or GtrR\n                    <jats:sup>R214A<\/jats:sup>\n                    , heme homeostasis was not perturbed, suggesting an alternative mechanism of heme synthesis regulation occurs in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    . In this regard, we report that heme synthesis is regulated through phosphorylation and dephosphorylation of GtrR by the serine\/threonine kinase Stk1 and the phosphatase Stp1, respectively. Taken together, these results suggest that the mechanisms governing staphylococcal heme synthesis integrate both the availability of heme and the growth status of the cell.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      represents a significant threat to human health. Heme is an iron-containing enzymatic cofactor that can be toxic at elevated levels. During infection,\n                      <jats:italic>S. aureus<\/jats:italic>\n                      must control heme levels to replicate and survive within the hostile host environment. We identified residues within a heme biosynthetic enzyme that are critical for heme binding\n                      <jats:italic>in vitro;<\/jats:italic>\n                      however, abrogation of heme binding is not sufficient to perturb heme homeostasis within\n                      <jats:italic>S. aureus<\/jats:italic>\n                      . This marks a divergence from previously reported mechanisms of heme-dependent regulation of the highly conserved enzyme glutamyl tRNA reductase (GtrR). Additionally, we link cell growth arrest to the modulation of heme levels through the post-translational regulation of GtrR by the kinase Stk1 and the phosphatase Stp1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00171-23","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T09:02:30Z","timestamp":1693558950000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":19,"title":["Maintenance of heme homeostasis in\n                    <i>Staphylococcus aureus<\/i>\n                    through post-translational regulation of glutamyl-tRNA reductase"],"prefix":"10.1128","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-3836","authenticated-orcid":true,"given":"Catherine S.","family":"Leasure","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , 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