Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase

  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},
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.



The porphobilinogen synthase family of metalloenzymes.

  • E. Jaffe
  • Biology
    Acta crystallographica. Section D, Biological crystallography
  • 2000
Novel crystal structures for three PBGS proteins coupled with more than 50 individual PBGS sequences allow an evaluation of assumptions regarding commonalities and the possibility that there may be up to four specific divalent metal ion-binding sites, each serving a unique function that can be alternatively filled by amino acids in some of the PBGSs.

High resolution crystal structure of a Mg2+-dependent porphobilinogen synthase.

The observed differences in the active sites of both monomers might be induced by Mg2+-binding to this remote site and a structure-based mechanism for this allosteric Mg 2+in rate enhancement is proposed.

An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase.

Characterization of the role of the stimulatory magnesium of Escherichia coli porphobilinogen synthase.

Mn(II) is a good substitute for Mgc, giving a comparable increase in catalytic activity, and has been used as an EPR active probe of the Mgc binding site, reflecting a single type of binding site with rhombic symmetry.

Pseudomonas aeruginosa contains a novel type V porphobilinogen synthase with no required catalytic metal ions.

Type V PBGS has the remarkable ability to synthesize porphobilinogen in a metal ion independent fashion, and the total metal ion stoichiometry of only 4 per octamer suggests half-sites reactivity.

Porphobilinogen synthase from pea: expression from an artificial gene, kinetic characterization, and novel implications for subunit interactions.

Analysis of the protein concentration dependence of the specific activity suggests that the minimal functional unit is a tetramer, and this is consistent with the protein undergoing conformational changes and the idea that whole-body motion can occur between subunits.

Production, purification, and characterization of a Mg2+-responsive porphobilinogen synthase from Pseudomonas aeruginosa.

Alteration of N-terminal amino acids changed the oligomeric state and reduced the activity of the enzyme, revealing the importance of this region for oligomerization and activity in tetrapyrrole biosynthesis.

X-ray structure of 5-aminolaevulinate dehydratase, a hybrid aldolase

Lead ions, which inhibit ALAD potently, replace the zinc bound to the enzyme's unique triple-cysteine site and therefore represents an intriguing combination of both metallo- and Schiff base-aldolases.

Mechanistic basis for suicide inactivation of porphobilinogen synthase by 4,7-dioxosebacic acid, an inhibitor that shows dramatic species selectivity.

4,7-Dioxosebacic acid was designed as an analogue of a proposed reaction intermediate in the physiological PBGS-catalyzed condensation of two molecules of 5-aminolevulinic acid and is the first structure to show inhibitor binding at the second of two substrate-binding sites.