Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase

@article{Breinig2003ControlOT,
  title={Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase},
  author={Sabine Breinig and Jukka Kervinen and Linda Stith and Andrew S Wasson and Robert Fairman and Alexander Wlodawer and Alexander S. Zdanov and Eileen K. Jaffe},
  journal={Nature Structural Biology},
  year={2003},
  volume={10},
  pages={757-763}
}
Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of tetrapyrroles (such as heme and chlorophyll). Although the predominant oligomeric form of this enzyme, as inferred from many crystal structures, is that of a homo-octamer, a rare human PBGS allele, F12L, reveals the presence of a hexameric form. Rearrangement of an N-terminal arm is responsible for this oligomeric switch, which results in profound changes in kinetic behavior. The structural transition between… 

The Remarkable Character of Porphobilinogen Synthase.

  • E. Jaffe
  • Biology, Chemistry
    Accounts of chemical research
  • 2016
The requirement for multimer dissociation as an intermediate step in PBGS allostery was established by monitoring subunit disproportionation during the turnover-dependent transition of heteromeric PBGS (comprised of human wild type and F12L) from hexamer to octamer, and one outcome was the definition of the dissociative morpheein model of proteinAllostery.

Allosteric Inhibition of Human Porphobilinogen Synthase*

The hypothesis that human PBGS hexamer stabilization may explain these side effects of lead poisoning and ALAD porphyria is supported, and the current work identifies allosteric ligands of human PB GS and, thus, identifies humanPBGS as a medically relevant allosterics enzyme.

Porphobilinogen synthase: An equilibrium of different assemblies in human health.

  • E. Jaffe
  • Biology
    Progress in molecular biology and translational science
  • 2020

The porphobilinogen synthase catalyzed reaction mechanism.

  • E. Jaffe
  • Chemistry, Biology
    Bioorganic chemistry
  • 2004

Probing the active site of Pseudomonas aeruginosa porphobilinogen synthase using newly developed inhibitors.

This study combines structural and kinetic evaluation of the inhibition potency of these inhibitors and can corroborate an earlier postulated enzymatic mechanism that starts with formation of a C-C bond, linking C3 of the A-side ALA to C4 of the P- side ALA through an aldole addition.

Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase

The crystal structure of TgPBGS, which contains an octamer in the crystallographic asymmetric unit, is solved and suggests strategies for the development of parasite-selective PBGS inhibitors.

Kinetics and thermodynamics of the interchange of the morpheein forms of human porphobilinogen synthase.

The free energy of activation for the conversion of WT+F12L human PBGS heterohexamers to hetero-octamers is determined to be the same as that for the catalytic conversion of substrate to product by the octamer, remarkably suggesting a common rate-limiting step for both processes.

Redox and metal-regulated oligomeric state for human porphobilinogen synthase activation

It is concluded that redox-regulated PBGS activation via cleavage of disulfide bonds among Cys122, Cys124, and Cys132 and coordination with zinc ion is closely linked to change in the oligomeric state.
...

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