The nickel-pincer nucleotide (NPN) coenzyme, a substituted pyridinium mononucleotide that tri-coordinates nickel, was first identified covalently attached to a lysine residue in the LarA protein of lactate racemase. Starting from nicotinic acid adenine dinucleotide, LarB carboxylates C5 of the pyridinium ring and hydrolyzes the phosphoanhydride, LarE converts the C3 and C5 carboxylates to thiocarboxylates, and LarC incorporates nickel to form a C–Ni and two S–Ni bonds, during the biosynthesis of this cofactor. LarB uses a novel carboxylation mechanism involving the transient formation of a cysteinyl-pyridinium adduct. Depending on the source of the enzyme, LarEs either catalyze a sacrificial sulfur transfer from a cysteinyl side chain resulting in the formation of dehydroalanine or they utilize a [4Fe–4S] cluster bound by three cysteine residues to accept and transfer a non-core sulfide atom. LarC is a CTP-dependent enzyme that cytidinylylates its substrate, adds nickel, then hydrolyzes the product to release NPN and CMP. Homologs of the four lar genes are widely distributed in microorganisms, with some species containing multiple copies of larA whereas others lack this gene, consistent with the cofactor serving other functions. Several LarA-like proteins were shown to catalyze racemase or epimerase activities using 2-hydroxyacid substrates other than lactic acid. Thus, lactate racemase is the founding member of a large family of NPN-containing enzymes.
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August 2022
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Intravital imaging of the pancreatic cancer microenvironment, highlighting fibrillar collagen (Second Harmonic Generation, cyan) and tumour vasculature (Quantum Dots, red). For further information, see the review in this issue by Murphy and colleagues (pages 1129–1141). Credit: Kendelle Murphy.
Review Article|
August 12 2022
Unveiling the mechanisms and biosynthesis of a novel nickel-pincer enzyme
Shramana Chatterjee;
Shramana Chatterjee
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, U.S.A.
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Santhosh Gatreddi;
Santhosh Gatreddi
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, U.S.A.
2Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, U.S.A.
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Swati Gupta;
Swati Gupta
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, U.S.A.
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Jorge L. Nevarez;
Jorge L. Nevarez
3Department of Chemistry, Michigan State University, East Lansing, MI 48824, U.S.A.
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Joel A. Rankin;
Joel A. Rankin
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, U.S.A.
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Aiko Turmo;
Aiko Turmo
2Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, U.S.A.
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Jian Hu
;
Jian Hu
2Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, U.S.A.
3Department of Chemistry, Michigan State University, East Lansing, MI 48824, U.S.A.
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Robert P. Hausinger
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, U.S.A.
2Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, U.S.A.
Correspondence: Robert P. Hausinger (hausinge@msu.edu)
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Biochem Soc Trans (2022) 50 (4): 1187–1196.
Article history
Received:
June 20 2022
Revision Received:
July 28 2022
Accepted:
July 29 2022
Citation
Shramana Chatterjee, Santhosh Gatreddi, Swati Gupta, Jorge L. Nevarez, Joel A. Rankin, Aiko Turmo, Jian Hu, Robert P. Hausinger; Unveiling the mechanisms and biosynthesis of a novel nickel-pincer enzyme. Biochem Soc Trans 31 August 2022; 50 (4): 1187–1196. doi: https://doi.org/10.1042/BST20220490
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