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… Expand
The Remarkable Character of Porphobilinogen Synthase.
  • E. Jaffe
  • Chemistry, Medicine
  • Accounts of chemical research
  • 2016
TLDR
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. Expand
Allosteric Inhibition of Human Porphobilinogen Synthase*
TLDR
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. Expand
Porphobilinogen synthase: An equilibrium of different assemblies in human health.
  • E. Jaffe
  • Medicine, Chemistry
  • Progress in molecular biology and translational science
  • 2020
TLDR
The dynamic multimerization of PBGS revealed the morpheein mechanism for allostery, a structural basis for inborn errors of metabolism, a quaternary structure focus for drug discovery and/or drug side effects, and a pathway toward new antibiotics or herbicides. Expand
Allostery and the dynamic oligomerization of porphobilinogen synthase.
TLDR
In silico and in vitro approaches have revealed species-specific allosteric PBGS inhibitors that stabilize the 6mer∗, leading to the hypothesis that extrinsicAllosteric inhibition of human PBGS could be a mechanism for drug side effects. Expand
Probing the oligomeric assemblies of pea porphobilinogen synthase by analytical ultracentrifugation.
TLDR
It is established that the distribution of pea PBGS quaternary structures also contains octamers and hexamers, using both sedimentation velocity and sedimentation equilibrium experiments and results in which the octamer dominates under purification conditions are reported. Expand
The porphobilinogen synthase catalyzed reaction mechanism.
  • E. Jaffe
  • Chemistry, Medicine
  • Bioorganic chemistry
  • 2004
TLDR
The reaction appears to stall at a covalently bound almost-product intermediate that is poised for breakdown to product upon binding of a substrate molecule to an adjacent active site and a subsequent conformational change. Expand
Probing the active site of Pseudomonas aeruginosa porphobilinogen synthase using newly developed inhibitors.
TLDR
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. Expand
Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase
TLDR
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. Expand
Tracking the evolution of porphobilinogen synthase metal dependence in vitro.
TLDR
This study delineates the potential evolutionary path between Zn (2+)-free and Zn( 2+)-dependent PBGS enyzmes showing that the rigid backbone of PBGS enzymes is an ideal framework to create or eliminate metal dependence through a limited number of amino acid exchanges. Expand
Kinetics and thermodynamics of the interchange of the morpheein forms of human porphobilinogen synthase.
TLDR
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. Expand
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