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2.
Bioorg Chem ; 100: 103836, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353563

RESUMO

In eucaryotic cells, methionine synthase reductase (MSR/MTRR) is capable of dominating the folate-homocysteine metabolism as an irreplaceable partner in electron transfer for regeneration of methionine synthase. The N-terminus of MTRR containing a conserved domain of FMN_Red is closely concerned with the oxidation-reduction process. Maternal substitution of I22M in this domain can bring about pregnancy with high risk of spina bifida. A new variation of Arg2del was identified from a female conceiving a fetus with spina bifida cystica. Although the deletion is far from the N-terminal FMN_Red domain, the biochemical features of the variant had been seriously investigated. Curiously, the deletion of arginine(s) of MTRR could not affect the electron relay, if only the FMN_Red domain was intact, but by degrees reduced the ability to promote MTR catalysis in methionine formation. Confirmation of the interaction between the isolated MTRR N-terminal polypeptide and MTR suggested that the native MTRR N-terminus might play an extra role in MTR function. The tandem arginines at the end of MTRR N-terminus conferring high affinity to MTR were indispensable for stimulating methyltransferase activity perhaps via triggering allosteric effect that could be attenuated by removal of the arginine(s). It was concluded that MTRR could also propel MTR enzymatic reaction relying on the tandem arginines at N-terminus more than just only implicated in electron transfer in MTR reactivation cycle. Perturbance of the enzymatic cooperation due to the novel deletion could possibly invite spina bifida in clinics.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Ferredoxina-NADP Redutase/metabolismo , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/química , Sequência de Aminoácidos , Transporte de Elétrons , Éxons , Ferredoxina-NADP Redutase/química , Ferredoxina-NADP Redutase/genética , Humanos , Modelos Moleculares , Conformação Proteica , Alinhamento de Sequência , Deleção de Sequência , Disrafismo Espinal/genética , Disrafismo Espinal/metabolismo
3.
Neuromolecular Med ; 19(2-3): 387-394, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28712006

RESUMO

Maternal genetic variants of enzymes in folate-homocysteine metabolic network are significantly correlative with the risk of spina bifida. To survey the genetic causality, the genotypes of three women having spina bifida fetuses from two unrelated Chinese families were screened in candidate alleles. Polymerase chain reaction, capillary electrophoresis and Sanger sequencing were employed to recognize the allelic variation. A trinucleotide deletion (c.4_6delAGG) was identified in the first exon of MTRR. All the three women showed the novel clinical variation including one heterozygous and two homozygous. The siblings who had healthy babies from the same families did not harbor the variation. In the unaffected control individuals, the variant was also not observed. Eukaryotic expression and bioinformatics techniques were utilized to explore the molecular pathogenesis of the potential genetic risk of developing spina bifida. Exceptionally, the functional examination revealed that the Arg2del variant kept subcellular localization unaltered with catalytic activity intact, but failed to efficiently activate MTR compared with the wild type. Genetic disorder of folate and homocysteine metabolism during pregnancy is believed to be associated with folate-sensitive neural tube defects. The report highlights that the inframe deletion in MTRR exon 1 could be a high risk factor susceptibility to spina bifida.


Assuntos
Éxons/genética , Ferredoxina-NADP Redutase/genética , Disrafismo Espinal/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Adulto , Sequência de Aminoácidos , Células Cultivadas , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Genótipo , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/genética , Recém-Nascido , Metilação , Modelos Moleculares , Gravidez , Complicações na Gravidez/genética , Conformação Proteica , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Deleção de Sequência , Adulto Jovem
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