8G64

Heme-bound flavodoxin FldH from Fusobacterium nucleatum

Summary for 8G64

• Entry DOI: 10.2210/pdb8g64/pdb
• Descriptor: Flavodoxin, FLAVIN MONONUCLEOTIDE, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• Functional Keywords: anaerobilin, fmn-containing flavodoxin, heme acquisition chaperone, hmuf homolog, flavoprotein
• Biological source: Fusobacterium nucleatum
• Total number of polymer chains: 1
• Total formula weight: 20768.49

Authors

Chan, A.C.,Wolthers, K.R.,Murphy, M.E. (deposition date: 2023-02-14, release date: 2023-08-09, Last modification date: 2024-05-22)

Primary citation

McGregor, A.K.,Chan, A.C.K.,Schroeder, M.D.,Do, L.T.M.,Saini, G.,Murphy, M.E.P.,Wolthers, K.R.
A new member of the flavodoxin superfamily from Fusobacterium nucleatum that functions in heme trafficking and reduction of anaerobilin.
J.Biol.Chem., 299:104902-104902, 2023

PubMed Abstract: Fusobacterium nucleatum is an opportunistic oral pathogen that is associated with various cancers. To fulfill its essential need for iron, this anaerobe will express heme uptake machinery encoded at a single genetic locus. The heme uptake operon includes HmuW, a class C radical SAM-dependent methyltransferase that degrades heme anaerobically to release Fe and a linear tetrapyrrole called anaerobilin. The last gene in the operon, hmuF encodes a member of the flavodoxin superfamily of proteins. We discovered that HmuF and a paralog, FldH, bind tightly to both FMN and heme. The structure of Fe-heme-bound FldH (1.6 Å resolution) reveals a helical cap domain appended to the ⍺/β core of the flavodoxin fold. The cap creates a hydrophobic binding cleft that positions the heme planar to the si-face of the FMN isoalloxazine ring. The ferric heme iron is hexacoordinated to His134 and a solvent molecule. In contrast to flavodoxins, FldH and HmuF do not stabilize the FMN semiquinone but instead cycle between the FMN oxidized and hydroquinone states. We show that heme-loaded HmuF and heme-loaded FldH traffic heme to HmuW for degradation of the protoporphyrin ring. Both FldH and HmuF then catalyze multiple reductions of anaerobilin through hydride transfer from the FMN hydroquinone. The latter activity eliminates the aromaticity of anaerobilin and the electrophilic methylene group that was installed through HmuW turnover. Hence, HmuF provides a protected path for anaerobic heme catabolism, offering F. nucleatum a competitive advantage in the colonization of anoxic sites of the human body.

PubMed: 37302554
DOI: 10.1016/j.jbc.2023.104902

Experimental method

X-RAY DIFFRACTION (1.6 Å)