Recent examples of α-ketoglutarate-dependent mononuclear non-haem iron enzymes in natural product biosyntheses

Abstract

Covering: up to 2018 α-Ketoglutarate (αKG, also known as 2-oxoglutarate)-dependent mononuclear non-haem iron (αKG-NHFe) enzymes catalyze a wide range of biochemical reactions, including hydroxylation, ring fragmentation, C-C bond cleavage, epimerization, desaturation, endoperoxidation and heterocycle formation. These enzymes utilize iron(ii) as the metallo-cofactor and αKG as the co-substrate. Herein, we summarize several novel αKG-NHFe enzymes involved in natural product biosyntheses discovered in recent years, including halogenation reactions, amino acid modifications and tailoring reactions in the biosynthesis of terpenes, lipids, fatty acids and phosphonates. We also conducted a survey of the currently available structures of αKG-NHFe enzymes, in which αKG binds to the metallo-centre bidentately through either a proximal- or distal-type binding mode. Future structure-function and structure-reactivity relationship investigations will provide crucial information regarding how activities in this large class of enzymes have been fine-tuned in nature.

Lipopeptide families at the interface between pathogenic and beneficialPseudomonas-plant interactions

“…Synteny analysis of BGCs for mycins and peptins production revealed a set of 2 or 3 convergent genes of unknown function that are found, in many producers, right upstream of the mycin cluster. The two first genes encode for, respectively, a putative membrane-anchored protein with a periplasmic JmjC-family hydroxylase domain (Gao et al 2018) and an unknown MFS efflux protein (DHA3 family; transporter classification TC 2.A.1.21). The third gene, absent from some clusters (e.g.…”

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

“…α-KG-Hals belong to the superfamily of α-ketoglutarate-dependent oxygenases (α-KGOs), a diverse family of enzymes that catalyzes hydroxylation, epoxidation, epimerization, demethylation, ring formation, C-C bond cleavage and desaturation reactions. [154,155] α-KG-Hals are structurally and mechanistically related to α-KG-oxygenases, which follow a radical mechanism via formation of a high valent and short-lived Fe IV = O ferryl intermediate ( Figure 1). [156,157] This intermediate is a powerful oxidant that abstracts an hydrogen from un-activated carbon-hydrogen bond creating a substrate radical and another Fe III -hydroxyl (or Chloride) intermediate.…”

“…There are some excellent reviews on the enzymology and halogenation mechanism of α-KG-Hal and α-KGO superfamily of enzymes for further reading. [154,155,177]…”

Phenylalanine meta‐Hydroxylase: A Single Residue Mediates Mechanistic Control of Aromatic Amino Acid Hydroxylation

“…Aromatic amino acid hydroxylases represent a small but important group of enzymes responsible for a series of metabolically essential transformations, including the hydroxylation of l ‐tyrosine, l ‐tryptophan or l ‐phenylalanine to yield l ‐DOPA, 5‐hydroxy‐ l ‐tryptophan or l ‐tyrosine, respectively . These non‐heme‐iron‐dependent enzymes bind their metal cofactor at the active site with one glutamate and two histidine residues, a binding mode that is also found in other non‐heme‐iron enzymes such as the α‐ketoglutarate‐dependent dioxygenases . A significant difference from other non‐heme‐iron‐dependent enzymes is the requirement for tetrahydropterin as an additional cofactor.…”