Student Posters 51st Lorne Proteins Conference 2026

Structural and functional investigation of DesC and DesD for the biosynthesis of novel multimeric siderophores (#343)

Jiarui Yan 1 , Rachel Codd 2 , Megan Maher 1 3
  1. School of Chemistry and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia
  2. School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia
  3. Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia

Iron is essential for virtually all life on Earth. However, in spite of its abundance in nature, iron remains poorly bioaccessible due to its low solubility. To sequester this vital resource, bacteria have evolved to produce a diverse group of iron-binding molecules referred to as siderophores.

Desferrioxamines (DFOs) are one of the most well-known groups of siderophores due to their applications in chelation therapy. They are peptide-like molecules characterised by a trimeric configuration, with each monomer containing a hydroxamic acid functional group. The two oxygen atoms of hydroxamic acid can form strong coordination bonds with the metal ion and give DFOs their high affinity and specificity for iron(III) binding.

The biosynthesis of DFOs is facilitated by the DesABCD enzyme cluster [1]. The biosynthetic pathway begins with the decarboxylation and hydroxylation of L-lysine catalysed by DesA and DesB, respectively. The intermediate produced can then be subjected to acylation by DesC to form the DFO monomers. Finally, through multiple rounds of condensation reactions catalysed by DesD, three DFO monomers are linked together via amide bonds to yield the trimeric DFOs. Of these enzymes, DesC and DesD have the highest substrate and product flexibilities, which are directly responsible for the diversity in the DFO family [2]. While a large number of different linear and macrocyclic DFOs have been identified, all analogues retained the trimeric configuration.

In 2025, DFOs with higher multimeric states have been discovered for the first time along with the capacity of DesD to facilitate their production [3]. However, due to the lack of relevant structural information of DesD, elucidating the mechanism behind its unprecedented degree of enzyme plasticity remains difficult. The complete absence of available structural data for DesC has also hindered the studies of its unique substrate and product flexibility. In this investigation, we aim to tackle these challenges by solving the crystal structures of DesC and DesD and assaying their activities, which could potentially lead to the biosynthesis of novel multimeric DFOs for applications including cancer radiotherapy. This poster will present our initial findings in working towards this goal.

  1. Barona-Gómez F., Wong U., Giannakopulos A. E., Derrick P. J., Challis G. L. (2004) “Identification of a Cluster of Genes That Directs Desferrioxamine Biosynthesis in Streptomyces Coelicolor M145”, J. Am. Chem. Soc., 126(50):16282-16283.
  2. Telfer T. J., Richardson-Sanchez T., Gotsbacher M. P., Nolan K. P., Tieu W., Codd R. (2019) “Analogues of Desferrioxamine B (DFOB) with New Properties and New Functions Generated Using Precursor-Directed Biosynthesis”, Biometals, 32(3):395-408.
  3. Nolan K. P., Rosser C. A., Wood J. L., Font J., Sresutharsan A., Wang J., Markham T. E., Ryan R. M., Codd R. (2025) “An Elastic Siderophore Synthetase and Rubbery Substrates Assemble Multimeric Linear and Macrocyclic Hydroxamic Acid Metal Chelators”, Chem. Sci., 16(5): 2180-2190.