Descrição bioquímica quântica do bolsão de interação do ÍON Zn2+ na enzima ALAD humana
The enzyme Delta Aminolevulinic Dehydratase (ALAD) is a cytosolic metalloproteinase essential in several biological processes since it participates in the second step in porphobilinogen formation pathway, a tetrapyrrolic precursor of heme and chlorophyll. This enzyme is very sensitive to heavy me...
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| Formato: | Dissertação |
| Idioma: | por |
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| Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/21908 |
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| Resumo: | The enzyme Delta Aminolevulinic Dehydratase (ALAD) is a cytosolic metalloproteinase
essential in several biological processes since it participates in the second step in
porphobilinogen formation pathway, a tetrapyrrolic precursor of heme and chlorophyll.
This enzyme is very sensitive to heavy metals and has traditionally been used as a biomarker
in lead poisoning. Its inhibition occurs when these heavy metals are replaced
inside the metal binding site. In human ALAD, Zinc (Zn2+) functionally occupies this site
and it is essential for coordination of two chains of aminolevulinic acid for the enzymatic
catalysis. Although many in vitro, in vivo and in silico works have already demonstrated
the importance of Zn2+ at that site, to the best of our knowledge, there isn’t any studies
on literature based on quantum approach in order to elucidate this interactions in more
details. Therefore, the aim of the present study was to analyse the missense mutations
that affect the zinc binding site and describe through quantum methods the energy interaction
between zinc and ALAD with greater accuracy using the method of Molecular
fractionation with conjugated caps (MFCC) by quantifying amino acid residues’ energy
positioned at 8.5 Å of distance with the ligand centroid. It was identified biochemical
changes in the monomeric structure of mutants, which result in decreased enzyme
activity. It were identified a total of 30 residues with a wide range of energy values.
The residues with significant (atractition or repulsion) values and functionally related to
enzymatic activity were: Lys199, Lys252, Cys122, Cys124 and Cys132; and those that
demonstrated relevance to the ion permanence inside the binding site were: Asp169,
Gly130, Gly133, Asp120 and Ser168. Thus, it could be concluded that in addition to
the nucleophilic groups (thiolates groups) from Cys122, Cys124 and Cys132, others
residues such as Asp169, Asp120 and Ser168 are fundamental in the catalytic pocket
composition, since they showed high attractive interaction energy with Zn2+ ion. |
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