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Sequence and Structural Motifs Controlling the Broad Substrate Specificity of the Mycobacterial Hormone-Sensitive Lipase LipN.

التفاصيل البيبلوغرافية
العنوان: Sequence and Structural Motifs Controlling the Broad Substrate Specificity of the Mycobacterial Hormone-Sensitive Lipase LipN.
المؤلفون: Schemenauer DE; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Pool EH; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Raynor SN; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Ruiz GP; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Goehring LM; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Koelper AJ; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Wilson MA; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Durand AJ Jr; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Kourtoglou EC; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Larsen EM; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Lavis LD; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia 20147, United States., Esteb JJ; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Hoops GC; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States., Johnson RJ; Department of Chemistry and Biochemistry, Butler University, Indianapolis, Indiana 46208, United States.
المصدر: ACS omega [ACS Omega] 2023 Mar 30; Vol. 8 (14), pp. 13252-13264. Date of Electronic Publication: 2023 Mar 30 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101691658 Publication Model: eCollection Cited Medium: Internet ISSN: 2470-1343 (Electronic) Linking ISSN: 24701343 NLM ISO Abbreviation: ACS Omega Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, [2016]-
مستخلص: Mycobacterium tuberculosis has a complex life cycle transitioning between active and dormant growth states depending on environmental conditions. LipN (Rv2970c) is a conserved mycobacterial serine hydrolase with regulated catalytic activity at the interface between active and dormant growth conditions. LipN also catalyzes the xenobiotic degradation of a tertiary ester substrate and contains multiple conserved motifs connected with the ability to catalyze the hydrolysis of difficult tertiary ester substrates. Herein, we expanded a library of fluorogenic ester substrates to include more tertiary and constrained esters and screened 33 fluorogenic substrates for activation by LipN, identifying its unique substrate signature. LipN preferred short, unbranched ester substrates, but had its second highest activity against a heteroaromatic five-membered oxazole ester. Oxazole esters are present in multiple mycobacterial serine hydrolase inhibitors but have not been tested widely as ester substrates. Combined structural modeling, kinetic measurements, and substitutional analysis of LipN showcased a fairly rigid binding pocket preorganized for catalysis of short ester substrates. Substitution of diverse amino acids across the binding pocket significantly impacted the folded stability and catalytic activity of LipN with two conserved motifs (HGGGW and GDSAG) playing interconnected, multidimensional roles in regulating its substrate specificity. Together this detailed substrate specificity profile of LipN illustrates the complex interplay between structure and function in mycobacterial hormone-sensitive lipase homologues and indicates oxazole esters as promising inhibitor and substrate scaffolds for mycobacterial hydrolases.
Competing Interests: The authors declare no competing financial interest.
(© 2023 The Authors. Published by American Chemical Society.)
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معلومات مُعتمدة: R15 GM110641 United States GM NIGMS NIH HHS
تواريخ الأحداث: Date Created: 20230417 Latest Revision: 20240518
رمز التحديث: 20240518
مُعرف محوري في PubMed: PMC10099132
DOI: 10.1021/acsomega.3c00534
PMID: 37065048
قاعدة البيانات: MEDLINE
الوصف
تدمد:2470-1343
DOI:10.1021/acsomega.3c00534