At least two types of pincer complexes are known to exist in biology. A metal‐pyrroloquinolone quinone (PQQ) cofactor was first identified in bacterial methanol dehydrogenase, and later also found in selected short‐chain alcohol dehydrogenases of other microorganisms. The PQQ‐associated metal can be calcium, magnesium, or a rare earth element depending on the enzyme sequence. Synthesis of this organic ligand requires a series of accessory proteins acting on a small peptide, PqqA. Binding of metal to PQQ yields an ONO‐type pincer complex. More recently, a nickel‐pincer nucleotide (NPN) cofactor was discovered in lactate racemase, LarA. This cofactor derives from nicotinic acid adenine dinucleotide via action of a carboxylase/hydrolase, sulfur transferase, and nickel insertase, resulting in an SCS‐type pincer complex. The NPN cofactor likely occurs in selected other racemases and epimerases of bacteria, archaea, and a few eukaryotes.
One co-crystal structure characterized to identify and quantify various non-covalent interactions with spectroscopy, X-ray crystallography and density functional theory computations.
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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