5vz0 | pdb_00005vz0
Crystal structure of Lactococcus lactis pyruvate carboxylase G746A mutant in complex with cyclic-di-AMP
Structural highlights
Function[A0A089XIW4_9LACT] Catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second.[PIRNR:PIRNR001594] Publication Abstract from PubMedCyclic di-3',5'-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism in Listeria monocytogenes by inhibiting its pyruvate carboxylase (LmPC), a biotin-dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT) activities. We report here structural, biochemical, and functional studies on the inhibition of Lactococcus lactis PC (LlPC) by c-di-AMP. The compound is bound at the dimer interface of the CT domain, at a site equivalent to that in LmPC, although it has a distinct binding mode in the LlPC complex. This binding site is not well conserved among PCs, and only a subset of these bacterial enzymes are sensitive to c-di-AMP. Conformational changes in the CT dimer induced by c-di-AMP binding may be the molecular mechanism for its inhibitory activity. Mutations of residues in the binding site can abolish c-di-AMP inhibition. In L. lactis, LlPC is required for efficient milk acidification through its essential role in aspartate biosynthesis. The aspartate pool in L. lactis is negatively regulated by c-di-AMP, and high aspartate levels can be restored by expression of a c-di-AMP-insensitive LlPC. LlPC has high intrinsic catalytic activity and is not sensitive to acetyl-CoA activation, in contrast to other PC enzymes. Structural and functional studies of pyruvate carboxylase regulation by cyclic di-AMP in lactic acid bacteria.,Choi PH, Vu TMN, Pham HT, Woodward JJ, Turner MS, Tong L Proc Natl Acad Sci U S A. 2017 Aug 14. pii: 201704756. doi:, 10.1073/pnas.1704756114. PMID:28808024[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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