Biotin sensing at the molecular level

Abstract

Biotin influences transcription in organisms from bacteria to humans. The enzyme, biotin protein ligase, which catalyzes post-transcriptional biotin addition to biotin-dependent carboxylases, plays a central roll in transmitting the demand for biotin to gene expression. The molecular mechanism of this communication in bacteria is well understood and involves competing protein:protein interactions. Biochemical measurements indicate that this competition is kinetically controlled. In humans, the biochemistry of biotin sensing at the transcriptional level is not well characterized. However, the biotin holoenzyme ligase (holocarboxylase synthetase) is proposed to both catalyze biotin addition to carboxylases and to histones in its metabolic and transcriptional roles, respectively. Control of human holocarboxylase synthetase function is, however, considerably more complex than the simple competitive protein protein interactions observed in bacterial systems.

FIGURE 1

The E. coli biotin regulatory system. BirA binds to substrates biotin and adenosine triphosphate to catalyze synthesis of biotinoyl-5′-AMP. The resulting enzyme-adenylate complex can either interact with the BCCP subunit of ACC or homodimerize to transfer biotin or repress transcription initiation, respectively. Adapted from (23).

FIGURE 2

The alternative protein:protein interactions formed by holoBirA (A). Models were created in MolMol (32) using pdb files 2ewn and a pdb file provided by Zachary Wood (University of Georgia). The alternative functions of HCS in post-translational addition of biotin to carboxylases or histones (B). The carboxylase and histone models were created using Pymol (33) with pdb files 2qf7 and 1kx5, respectively.

FIGURE 3

The proposed biotin cycle in which biotin is first consumed and transported into cells, where it is linked to either biotin-dependent carboxylases or histone proteins in nucleosomes. Upon turnover of the biotinylated proteins, biocytin is released and hydrolyzed by biotinidase. The resulting free biotin reenters the biotin cycle.