Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Mol Genet Metab. 2012 Jan;105(1):44-55. doi: 10.1016/j.ymgme.2011.09.028. Epub 2011 Oct 1.
Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-phosphate uridylyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism. While the neonatal morbidity and mortality of the disease are now mostly prevented by newborn screening and galactose restriction, long-term outcome for older children and adults with this disorder remains unsatisfactory. The pathophysiology of Classic Galactosemia is complex, but there is convincing evidence that galactose-1-phosphate (gal-1P) accumulation is a major, if not the sole pathogenic factor. Galactokinase (GALK) inhibition will eliminate the accumulation of gal-1P from both dietary sources and endogenous production, and efforts toward identification of therapeutic small molecule GALK inhibitors are reviewed in detail. Experimental and computational high-throughput screenings of compound libraries to identify GALK inhibitors have been conducted, and subsequent studies aimed to characterize, prioritize, as well as to optimize the identified positives have been implemented to improve the potency of promising compounds. Although none of the identified GALK inhibitors inhibits glucokinase and hexokinase, some of them cross-inhibit other related enzymes in the GHMP small molecule kinase superfamily. While this finding may render the on-going hit-to-lead process more challenging, there is growing evidence that such cross-inhibition could also lead to advances in antimicrobial and anti-cancer therapies.
经典半乳糖血症是一种常染色体隐性遗传病，由半乳糖-1-磷酸尿苷酰转移酶（GALT）缺乏引起，该酶是半乳糖代谢 Leloir 途径中的关键酶之一。虽然通过新生儿筛查和限制半乳糖摄入，该疾病的新生儿发病率和死亡率现在已得到大部分预防，但该疾病年长儿童和成人的长期预后仍不尽人意。经典半乳糖血症的病理生理学较为复杂，但有确凿证据表明，半乳糖-1-磷酸（gal-1P）的积累是主要的（如果不是唯一的）致病因素。半乳糖激酶（GALK）抑制剂将消除饮食来源和内源性产生的 gal-1P 的积累，详细综述了鉴定治疗性小分子 GALK 抑制剂的研究进展。已经进行了化合物库的实验和计算高通量筛选，以鉴定 GALK 抑制剂，随后进行了旨在对鉴定出的阳性物进行特征描述、优先级排序和优化以提高有前途的化合物活性的研究。虽然鉴定出的 GALK 抑制剂都不抑制葡萄糖激酶和己糖激酶，但其中一些抑制剂会交叉抑制 GHMP 小分子激酶超家族中的其他相关酶。虽然这一发现可能会使当前的从命中枢到先导的过程更加具有挑战性，但越来越多的证据表明，这种交叉抑制也可能会推进抗菌和抗癌疗法的进展。
