New insights into copper monooxygenases and peptide amidation: structure, mechanism and function

@article{Prigge2000NewII,
  title={New insights into copper monooxygenases and peptide amidation: structure, mechanism and function
},
  author={Sean T. Prigge and Richard E. Mains and Betty A. Eipper and L. Mario Amzel},
  journal={Cellular and Molecular Life Sciences CMLS},
  year={2000},
  volume={57},
  pages={1236-1259}
}
Abstract. Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-Cα bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine α-amidating monooxygenase (PAM). The PAM gene encodes… 

Peptidylglycine α‐Hydroxylating Monooxygenase (PHM)

TLDR
The structure and function of PHM have been broadly studied, the pathway of its electron transfer, the nature of the metal-oxygen species, and details of the mechanism are still being investigated.

Peptidyl‐α‐Hydroxyglycine α‐Amidating Lyase (PAL)

TLDR
The X-ray crystal structure of the PAL catalytic core (PALcc), alone and in complex with the nonpeptidic substrate α-hydroxyhippuric acid, shows that PAL folds as a six-bladed β-propeller.

Evidence for substrate preorganization in the peptidylglycine α-amidating monooxygenase reaction describing the contribution of ground state structure to hydrogen tunneling.

TLDR
The authors' data show that all Ν-acylglycines bind sequentially to PHM in an equilibrium-ordered fashion, and the decrease in KIE with hydrophobicity was attributed to a preorganization event which decreased reorganization energy by decreasing the conformational sampling associated with ground state substrate binding.

Reaction Mechanism of the Bicopper Enzyme Peptidylglycine α-Hydroxylating Monooxygenase*

TLDR
A computational study proposes a new mechanism for the reaction mechanism of Peptidylglycine α-hydroxylating monooxygenase, suggesting that the most likely abstracting species is [CuOOH]2+.

Coordination of peroxide to the CuM center of peptidylglycine α-hydroxylating monooxygenase (PHM): structural and computational study

TLDR
The structure of the oxidized form of PHM complexed with hydrogen peroxide is determined and the geometry of the observed side-on coordinated peroxide ligand in L3CuM(II)O22− is in good agreement with the results of a hybrid quantum mechanical–molecular mechanical optimization of this species.

Probing the Production of Amidated Peptides following Genetic and Dietary Copper Manipulations

TLDR
The first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo is provided, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates.

The catalytic copper of peptidylglycine alpha-hydroxylating monooxygenase also plays a critical structural role.

TLDR
Structural and calorimetric studies point to a structural role for the CuM site, in addition to its established catalytic role, in the Peptidylglycine alpha-hydroxylating monooxygenase mutant.

HHM motif at the CuH-site of peptidylglycine monooxygenase is a pH-dependent conformational switch.

TLDR
The results establish that M109 is indeed the coordinating ligand and confirm the prediction that the low pH structural transition with associated loss of activity is abrogated when the M109 thioether is absent, suggesting a more general utility for the HHM motif as a copper- and pH-dependent conformational switch.

Peptide amidation: Production of peptide hormonesin vivo andin vitro

TLDR
This review presents the current situation regarding amidation, with a special emphasis on the industrial production of peptide hormones, as well as various strategies utilizing PAM, carboxypeptidase-Y enzymes, and chemical synthesis for producing peptide amidesin vitro.
...

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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
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TLDR
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TLDR
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TLDR
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