The Molecular Mechanism of Lead Inhibition of Human Porphobilinogen Synthase*

@article{Jaffe2001TheMM,
  title={The Molecular Mechanism of Lead Inhibition of Human Porphobilinogen Synthase*},
  author={Eileen K Jaffe and Jacob Martins and Jing Li and Jukka Kervinen and Roland L. Dunbrack},
  journal={The Journal of Biological Chemistry},
  year={2001},
  volume={276},
  pages={1531 - 1537}
}
Human porphobilinogen synthase (PBGS) is a main target in lead poisoning. Human PBGS purifies with eight Zn(II) per homo-octamer; four ZnA have predominantly nonsulfur ligands, and four ZnB have predominantly sulfur ligands. Only four Zn(II) are required for activity. To better elucidate the roles of Zn(II) and Pb(II), we produced human PBGS mutants that are designed to lack either the ZnA or ZnB sites. These proteins, MinusZnA (H131A, C223A) and MinusZnB (C122A, C124A, C132A), each become… Expand
Redox and metal-regulated oligomeric state for human porphobilinogen synthase activation
TLDR
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. 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
Species-specific Inhibition of Porphobilinogen Synthase by 4-Oxosebacic Acid*
TLDR
It is shown that 4-OSA is an active site-directed irreversible inhibitor for Escherichia coli PBGS, whereas human, pea, Pseudomonas aeruginosa, andBradyrhizobium japonicum PBGS are insensitive to inhibition by 4- OSA. Expand
An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase.
  • E. Jaffe
  • Medicine, Chemistry
  • Chemistry & biology
  • 2003
TLDR
The phylogenetic distribution of PBGS metal ion utilization suggests that the primordial PBGS required zinc and supports a hypothesis that the loss of the zinc site was concurrent with the advent of oxygenic photosynthesis. Expand
pH-Dependent Coordination of Pb2+ to Metallothionein2: Structures and Insight into Lead Detoxification
TLDR
Lead is a toxic heavy metal whose detoxification in organisms is mainly carried out by its coordination with some metalloproteins such as metallothioneins (MTs), but the structures of the two complexes, which are crucial for a better understanding of the detoxification mechanism of Pb–MTs, have not been clearly elucidated. Expand
Exploring human porphobilinogen synthase metalloprotein by quantum biochemistry and evolutionary methods†.
TLDR
DFT-based models within the molecular fragmentation with conjugate caps (MFCC) scheme were used to evaluate the binding energy features of zinc interacting with the Human PBGS and show that the processing time dependence is more associated with the choice of the basis set than the exchange-correlation functional. Expand
A Structural Basis for Half-of-the-sites Metal Binding Revealed in Drosophila melanogaster Porphobilinogen Synthase*
TLDR
A structural basis for half-of-the-sites metal binding that is consistent with a reciprocating motion model for function of oligomeric PBGS is revealed. Expand
The activation mechanism of human porphobilinogen synthase by 2-mercaptoethanol: intrasubunit transfer of a reserve zinc ion and coordination with three cysteines in the active center
TLDR
Findings suggest that a distal zinc ion moved to the proximal binding site when a disulfide bond among Cys122, Cys124 and Cys132 was reduced by reductants. 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
Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase
TLDR
The unprecedented structural rearrangement reported here relates to the allosteric regulation of PBGS and suggests that alternative PBGS oligomers may function in a magnesium-dependent regulation of tetrapyrrole biosynthesis in plants and some bacteria. Expand
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References

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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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. Expand
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TLDR
Porphobilinogen is the monopyrrole precursor of all biological tetrapyrroles and some bacterial and plant PBGS may use magnesium in place of one or both of the zinc ions of mammalian PBGS, and phylogenetic variations in metal ion usage are described. Expand
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TLDR
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High resolution crystal structure of a Mg2+-dependent porphobilinogen synthase.
TLDR
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. Expand
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TLDR
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An Artificial Gene for Human Porphobilinogen Synthase Allows Comparison of an Allelic Variation Implicated in Susceptibility to Lead Poisoning*
TLDR
An artificial gene encoding human PBGS was constructed by recursive polymerase chain reaction from synthetic oligonucleotides to rectify this problem and to remove rare codons that can confound heterologous protein expression in E. coli. Expand
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