biostudies-literatureGupta PNIAID NIH HHSNational Institutes of HealthBill and Melinda Gates FoundationWellcome TrustNIGMS NIH HHS3491-3506https://www.ebi.ac.uk/biostudies/studies/S-EPMC8220418biostudies-literatureUnknown19The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of <i>Mycobacterium tuberculosis</i> are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic <i>M. tuberculosis</i> infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confComputational and structural biotechnology journalA fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt;.PMC8220418200814SC1 GM140968R37 AI026170200814/Z/16/ZThomas SEJacobs WRZaidan SABurgess APasillas MATiwari SMendes VCattermole EBlundell TLCory-Wright JAbell CMeghir CCoyne AGSebastian-Perez VGupta PfalseA fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt;.The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of <i>Mycobacterium tuberculosis</i> are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic <i>M. tuberculosis</i> infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further conf2021-01-01T00:00:00Z20212026-05-08T18:55:30.292Z2022-02-10T17:39:25.878ZS-EPMC82204183419467310.1016/j.csbj.2021.06.006