Desferrioxamine biosynthesis: diverse hydroxamate assembly by substrate-tolerant acyl transferase DesC

Abstract

Hydroxamate groups play key roles in the biological function of diverse natural products. Important examples include trichostatin A, which inhibits histone deacetylases via coordination of the active site zinc(II) ion with a hydroxamate group, and the desferrioxamines, which use three hydroxamate groups to chelate ferric iron. Desferrioxamine biosynthesis in species involves the DesD-catalysed condensation of various-acylated derivatives of -hydroxycadaverine with two molecules of-succinyl--hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various -acyl--hydroxycadaverine substrates of DesD from -hydroxycadaverine has until now been unclear. Here we show that the gene of encodes the acyl transferase responsible for this process. DesC catalyses the-acylation of -hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the diverse array of desferrioxamines produced by The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of -succinyl--hydroxycadaverine and one of -acetyl--hydroxycadaverine) was also determined. This showed that the acetyl group of ferrioxamine B is solvent exposed, suggesting that the corresponding acyl group in longer chain congeners can protrude from the binding pocket, providing insights into their likely function. This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

Novel South African Rare Actinomycete Kribbella speibonae Strain SK5: A Prolific Producer of Hydroxamate Siderophores Including New Dehydroxylated Congeners

“…Biosynthesis of the desferrioxamine class of hydroxamate siderophores has been elucidated in Streptomyces and is mediated by nonribosomal peptide synthetase-independent siderophore (NIS) synthetases [9,10,25,26]. Every NIS biosynthetic pathway identified to date contains at least one synthetase with a high sequence similarity to IucA/IucC and such synthetases have thus become the characteristic feature of these pathways [10].…”

“…In silico analysis of the annotated genome of the K. speibonae strain SK5 (GenBank accession number: SJJY00000000) identified the biosynthetic gene cluster (BGC) encoding the IucA/IucC synthetase that is likely responsible for producing 1-6 ( Figure 3A, Table 1). The desferrioxamine (des) BGC in Streptomyces coelicolor strain M145 was proposed to comprise four genes, desABCD [25]. The spbA and spbB genes in the K. speibonae strain SK5 encode enzymes having a high sequence similarity to pyridoxal 5′-phosphate (PLP)-dependent decarboxylase and lysine-6-monooxygenase in Streptomyces strains, respectively [27].…”

“…It is proposed that the common decarboxylation intermediate, cadaverine 18, undergoes spontaneous SpbC-catalyzed acylation, followed by SpbDand SpbE-catalyzed oligomerization of two molecules of succinate, two molecules of N-acetylcadaverine, and one molecule of cadaverine to generate 1. The desferrioxamine (des) BGC in Streptomyces coelicolor strain M145 was proposed to comprise four genes, desABCD [25]. The spbA and spbB genes in the K. speibonae strain SK5 encode enzymes having a high sequence similarity to pyridoxal 5 -phosphate (PLP)-dependent decarboxylase and lysine-6-monooxygenase in Streptomyces strains, respectively [27].…”

Pharmaceutical Targeting the Envelope Protein of SARS-CoV-2: the Screening for Inhibitors in Approved Drugs

“…For the docking, deferoxamine-Fe 3+ complex (known as desferrioxamine B) was extracted from the Xray structure of its assembly with an acyl transferase (PDB 6ENK [27]). It has also served as a template to model the complex of nocardamine-Fe 3+ (desferrioxamine E).…”

Iron-meditated fungal starvation by lupine rhizosphere-associated and extremotolerant Streptomyces sp. S29 desferrioxamine production

“…The biosynthetic machinery of desferrioxamines has been well studied [19][20][21] and as a consequence, the chemical potential continues to expand. The substrate specificity of DesC-like proteins, similar to acyl CoA-dependent transferases, seems to be the key factor in producing diverse desferrioxamine scaffolds.…”