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首页> 外文期刊>RSC Advances >Disturbed cofactor binding by a novel mutation in UDP-galactose 4′-epimerase results in a type III galactosemia phenotype at birth
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Disturbed cofactor binding by a novel mutation in UDP-galactose 4′-epimerase results in a type III galactosemia phenotype at birth

机译：由UDP-半乳糖4'-映酶的新突变在出生时产生III型半乳糖虫表型的新突变的官方粘接剂结合

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UDP-galactose 4′-epimerase (GALE) is an essential enzyme in galactose metabolism and its dysfunction results in type III galactosemia. Herein we report a patient born with abnormal blood galactose levels and reduced GALE activity who was shown to be heterozygous for a c.266C>T missense mutation in the GALE gene, predicted to result in the amino acid exchange p.A89V. Over a period of months, the patient's blood galactose, galactose 1-phosphate and GALE activity levels reverted to normal, encouraging us to investigate this mutation. Structurally Ala89 is a highly conserved residue located close to the binding site of the cofactor, NAD ~(+) . Consequentially molecular modelling predicted that this mutation results in steric clashes between the cofactor and valine side chain, and bioinformatic predictions suggested that p.A89V is likely to be less stable than the wild-type. Biochemical studies on the recombinant p.A89V enzyme demonstrated lower activity than the wild type ( K _(m) increased by approximately 30-fold; k _(cat) reduced approximately 180-fold), and additionally changes in stability and altered NAD ~(+) binding were observed. Thus, a picture emerges in which this mutation leads to reduced stability, disturbed cofactor binding and subsequently reduced activity. Overall this study suggests that bioinformatics predictions are useful in assessing the effects of newly discovered mutations on enzyme function, but care should be taken in extending predictions to the clinical phenotype especially in cases of heterozygosity. It also raises interesting questions about a dominant negative effect of some GALE missense alleles and potential compensatory mechanisms occurring in people born with clinical chemistry measurements suggesting a diagnosis of galactosemia.
机译：UDP-半乳糖4'-截止酶（GALE）是半乳糖代谢的基本酶及其功能障碍导致III型半乳糖瘤。在此，我们报告了出生的血液半乳糖水平的患者，并且降低的大疱性活性被显示为杂合的杂合在大脑基因中，预测导致氨基酸交换P.A89V。在几个月内，患者的血液半乳糖，半乳糖1-磷酸盐和大疱活性水平恢复正常，鼓励我们调查这种突变。结构上ALA89是高度保守的残余物，其靠近辅因子的粘结位点，NAD〜（+）。因此，分子建模预测，该突变导致辅因子和缬氨酸侧链之间的空间冲突，并且生物信息化预测表明P.A89V可能比野生型稳定。重组P.A89V酶的生化研究证明的活性低于野生型（K _（m）增加约30倍; K _（猫）减少约180倍），并且另外变化稳定性和变化的NAD〜 （+）被观察到结合。因此，出现了该突变导致降低稳定性，干扰的辅因子结合和随后减少活性的图像。总体而言，该研究表明，生物信息学预测可用于评估新发现的酶突变对酶功能的影响，但应注意将预测扩展到临床表型，特别是在杂合子的情况下。它还提出了关于一些大脑畸发等位基因的主导负面影响的有趣问题以及临床化学测量的人们发生的潜在补偿机制，表明患有半乳糖瘤的诊断。

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