Introduction to this second series of Biometals webinars, The biology of mammalian multi-copper ferroxidases, Arsenic antibiotics: old and new
Authors: Michaud-Soret Isabelle , Frazer David , Rosen Barry P. 
Published: February 2024

The biology of mammalian multi-copper ferroxidases

The mammalian multi-copper ferroxidases comprise a family of conserved enzymes that are essential for body iron homeostasis. Their main function is to ensure the efficient release of iron from body cells, and they facilitate this process by oxidising ferrous iron to its ferric form, allowing iron to be effectively exported from tissues via the protein channel ferroportin. There are currently three mammalian multi-copper ferroxidases, ceruloplasmin, hephaestin and zyklopen, with each predicted to contain six biosynthetically incorporated copper atoms which act as intermediate electron acceptors. Ceruloplasmin is found predominantly in the circulation as a secreted protein and is particularly important in facilitating iron release from the liver. It also exists as a GPI-linked membrane-bound form in the central nervous system where it plays a role in brain iron homeostasis. In contrast, both hephaestin and zyklopen are attached to cellular membranes via a single C-terminal transmembrane domain. Hephaestin is predominantly expressed in the enterocytes of the gastrointestinal tract and is essential for the efficient absorption of dietary iron. While the function of zyklopen is less well understood, it appears to be important for normal hair development, although the precise role played is not known. There is also some evidence that these proteins may have other, non-iron-related physiological functions, however, these are poorly described. In this presentation, I will compare and contrast the biological roles of the mammalian multi-copper ferroxidases and present some of our latest data on this important group of enzymes.

Arsenic antibiotics: old and new

Bacteria compete for survival in microbial jungles. It's like Jeff Goldblum says in Jurassic Park: "Life, uh, finds a way,'" Most organisms just try to survive living in arsenic. But some have found ways to use organoarsenicals as weapons against other bacteria in the continual battle for dominance in microbial warfare, while others find ways to fight back. Life always finds a way!

This presentation will briefly describe the plethora of ars proteins and their roles in biology and medicine. Arsenic has been a ubiquitous toxin since life first arose nearly 4 Bya in primordial anoxic oceans. In response to this environmental challenge, early organisms evolved genes/proteins for resistance pathways that transport and biotransform arsenic. Since we cloned the first arsenic operon in 1983, nearly every letter of the English alphabet has been utilized in the naming of ars genes. They encode a wide variety of enzymes, regulators and transport proteins. To date, nearly 30 genes with demonstrated functions have been identified in ars operons.

Even more striking is the ability of microbes to utilize this toxic metalloid to gain a competitive advantage over other microbes. Early in evolution, bacteria evolved the arsM gene encoding the ArsM As(III) S-adenosylmethionine (SAM) methyltransferase, which catalyzes methylation of inorganic arsenic to form highly toxic methylarsenite (MAs(III)), which has antibiotic properties in extant microbial communities. MAs(III) producers used as an antibiotic to kill off competitors. In response, other members of microbial communities evolved a variety of genes/proteins for transforming methylarsenicals into less toxic forms, i.e., antibiotic resistance. After the Great Oxidation Event (GOE), there was an expansion of genes/proteins that could use oxygen for arsenic biotransformations, and a number of those evolved into MAs(III) resistances.

A more recent example of the adaptation of arsenic as a weapon in microbial warfare is synthesis of the natural product arsinothricin (2-amino-4-(hydroxymethylarsinoyl)butanoic acid or AST) by the soil bacterium Burkholderia gladioli GSRB05. AST is a nonproteogenic amino acid that has broad-spectrum antibiotic action and is effective against both gram-positive and gram-negative bacteria, including some of the most dangerous human pathogens. Most recently we demonstrated that AST effectively inhibits both Plasmodium erythrocytic proliferation and parasite transmission to mosquitoes, We propose that AST is a promising lead compound for developing a new class of multi-stage antimalarials.