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We demonstrated that GmhA homologs in <jats:italic>Neisseria gonorrhoeae<\/jats:italic> and <jats:italic>N.\u00a0meningitidis<\/jats:italic> (hereafter called Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>GC<\/jats:sub><\/jats:styled-content> and Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>NM<\/jats:sub><\/jats:styled-content>, respectively) were interchangeable proteins essential for lipooligosaccharide (<jats:styled-content style=\"fixed-case\">LOS<\/jats:styled-content>) synthesis, and their depletion had adverse effects on neisserial viability. In contrast, the <jats:italic>Escherichia coli<\/jats:italic> ortholog failed to complement Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>GC<\/jats:sub><\/jats:styled-content> depletion. Furthermore, we showed that Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>GC<\/jats:sub><\/jats:styled-content> is a cytoplasmic enzyme with induced expression at mid\u2010logarithmic phase, upon iron deprivation and anaerobiosis, and conserved in contemporary gonococcal clinical isolates including the 2016 <jats:styled-content style=\"fixed-case\">WHO<\/jats:styled-content> reference strains. The untagged Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>GC<\/jats:sub><\/jats:styled-content> crystallized as a tetramer in the closed conformation with four zinc ions in the active site, supporting that this is most likely the catalytically active conformation of the enzyme. Finally, site\u2010directed mutagenesis studies showed that the active site residues E65 and H183 were important for <jats:styled-content style=\"fixed-case\">LOS<\/jats:styled-content> synthesis but not for Gmh<jats:styled-content style=\"fixed-case\">A<jats:sub>GC<\/jats:sub><\/jats:styled-content> function in bacterial viability. Our studies bring insights into the importance and mechanism of action of GmhA and may ultimately facilitate targeting the enzyme with small molecule inhibitors.<\/jats:p>","DOI":"10.1002\/mbo3.432","type":"journal-article","created":{"date-parts":[[2017,1,7]],"date-time":"2017-01-07T05:06:51Z","timestamp":1483765611000},"source":"Crossref","is-referenced-by-count":18,"title":["Functional and structural studies on the <i>Neisseria gonorrhoeae<\/i> GmhA, the first enzyme in the <i>glycero\u2010manno<\/i>\u2010heptose biosynthesis pathways, demonstrate a critical role in lipooligosaccharide synthesis and gonococcal viability"],"prefix":"10.1002","volume":"6","author":[{"given":"Igor H.","family":"Wierzbicki","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  Corvallis OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard A.","family":"Zielke","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  Corvallis OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin V.","family":"Korotkov","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cellular Biochemistry College of Medicine University of Kentucky  Lexington KY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7977-2596","authenticated-orcid":false,"given":"Aleksandra E.","family":"Sikora","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Oregon State University  Corvallis OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01396-9"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04013.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1128\/iai.20.1.228-234.1978","article-title":"Degradation of the polysaccharide component of gonococcal lipopolysaccharide by gonococcal and meningococcal sonic extracts","volume":"20","author":"Apicella M. 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