Structural insights into the ligand recognition and catalysis of the key aminobutanoyltransferase CntL in staphylopine biosynthesis

Abstract

Transition metals are indispensable nutrients for all cellular life and are frequently incorporated into metalloproteins to serve as essential cofactors. 1 The competition between pathogens and human cells for transition metals is an important component of the pathogenesis of infectious diseases, and hosts have developed a strategy known as "nutritional immunity" to restrict the pathogens from accessing essential transition metals to prevent microbial infection. 2 Bacteria have evolved various systems to subvert metal sequestration: elemental metal import, extracellular metal capture by metallophores, and metal acquisition from host metalloproteins, and these systems vary among species. [3][4] Metallophores are high-affinity

Arabidopsis Nicotianamine Synthases (NAS) comprise a common core-NAS domain fused to a variable auto-inhibitory C-terminus

“…In the bacterial NAS-like protein Staphylococcus aureus CntL that comprises merely a core-NAS domain, Luo et al (38) identified a linker region between its N- and C-terminal domain which is capable of conformational alternation between the open and closed states of SaCntL. The authors suggest that this linker region could have pivotal roles in allowing substrate entry, substrate recognition, and catalysis.…”

S-Adenosylmethionine: more than just a methyl donor

“…51 Both MtNAS and CntL possess a Rossmann fold MT C-terminal domain with a characteristic glycine-rich motif that binds SAM as the ACP donor. 45,51 An open to closed conformational change upon substrate binding was noted for CntL and involves the partially disordered interdomain linker in the CntL-SAM binary complex becoming an ordered a-helix in the CntL-MTA-xNA ternary complex. 51 The mechanism of CntL catalyzed ACP transfer is otherwise analogous to that of MtNAS.…”

“…45,51 An open to closed conformational change upon substrate binding was noted for CntL and involves the partially disordered interdomain linker in the CntL-SAM binary complex becoming an ordered a-helix in the CntL-MTA-xNA ternary complex. 51 The mechanism of CntL catalyzed ACP transfer is otherwise analogous to that of MtNAS. In addition to NAS and CntL, many other NAS-like enzymes have been identied or proposed in the biosynthesis of structurally diverse metallophores with an amino group serving as the acceptor nucleophile, which underscores the importance of SAM-dependent ACP modication of metallophores in bacteria.…”

“…51 Both MtNAS and CntL possess a Rossmann fold MT C-terminal domain with a characteristic glycine-rich motif that binds SAM as the ACP donor. 45,51 An open to closed conformational change upon substrate binding was noted for CntL and involves the partially disordered interdomain linker in the CntL–SAM binary complex becoming an ordered α-helix in the CntL–MTA–xNA ternary complex. 51 The mechanism of CntL catalyzed ACP transfer is otherwise analogous to that of MtNAS.…”

The Key Element Role of Metallophores in the Pathogenicity and Virulence of Staphylococcus aureus: A Review

“…Another study confirmed that during the synthesis of staphylopine, CntL stereoselectively carries out the catalysis of D-histidine and not L-histidine. These findings provided critical structural and mechanistic insights into CntL for a better understanding of of nicotianamine-like metallophores biosynthesis and the discovery of inhibitors of this process [ 92 ]. Concerning CntA, responsible for the recognition and transport of diverse solutes, a study was performed to investigate the structural conformation upon staphylopine binding.…”