Type IV galactosemia
Type IV galactosemia
复制标题
IV型半乳糖血症
作者：
D. Timson
这篇评论探讨了最近发现的一种新的半乳糖血症形式的一些影响。自1908年以来，这种疾病就被发现了。在二十世纪，半乳糖血症的分子基础是通过两条平行的调查线。首先，Leloir及其同事的开创性工作阐明了单糖半乳糖代谢的途径。其次，各种遗传学研究表明，半乳糖血症是一种遗传性代谢疾病。半乳糖不能直接进入糖酵解途径。要代谢，它在四个酶催化步骤中转化为葡萄糖6-磷酸。首先，在半乳糖激酶（GALK 1）催化的反应中，糖以三磷酸腺苷（ATP）为代价被磷酸化。所得半乳糖1-磷酸与UDP-葡萄糖反应，产生葡萄糖1-磷酸和UDP-半乳糖。该反应由半乳糖1-磷酸尿苷酰转移酶（GALT）催化。UDP半乳糖4 '-差向异构酶（GALE）通过催化UDP半乳糖的异构化而使UDP-葡萄糖再生。第二个异构化反应（由磷酸葡萄糖变位酶催化）将葡萄糖1-磷酸转化为糖酵解中间体葡萄糖6-磷酸。由GALK 1、GALT和GALE催化的反应是Leloir途径的核心反应。GALK 1具有高度的位点特异性和立体特异性。仅作用于D-半乳糖的α-端基异构体，生成α-D-半乳糖1-磷酸。然而，在溶液中，半乳糖在α和β-端基异构体之间平衡存在。虽然这两种端基异构体在水溶液中确实相互转化，但α-D-半乳糖的利用率可以超过其生成率。半乳糖变旋酶（醛糖1-差向异构酶，GALM）催化这一反应，具有令人印象深刻的周转数（人类酶为12，000 s）。这确保了Leloir途径被供应有足够量的α-D-半乳糖。在1956年，它被证明，半乳糖血症可以与遗传突变的GALT基因。虽然这是该疾病最常见的形式，但编码Leloir途径中其他酶的基因突变也可导致半乳糖血症。因此，GALT缺乏症被称为经典半乳糖血症或I型半乳糖血症（OMIM 230400）。II型半乳糖血症（OMIM 230200;发现于1967年）由GALK 1基因突变引起。1981年，III型半乳糖血症或GALE缺乏症（OMIM 230350）被发现。半乳糖血症有非常广泛的症状，从几乎没有表型到危及生命的代谢紊乱。最严重的形式，即使通过从饮食中去除半乳糖及其前体来治疗，也几乎总是导致严重的身体残疾和认知障碍。这种变异主要是由于大量可能导致该疾病的突变造成的--目前已知的突变超过300种。通常，GALT突变与更严重的疾病形式有关，这些疾病在儿童早期表现出来，并导致肝脏，大脑和卵巢损伤。相比之下，II型半乳糖血症的后果要轻得多，其中早发性白内障最常见。III型半乳糖血症可能具有最广泛的症状。最轻微的形式几乎没有症状，而最严重的形式与I型有相似的症状。自从发现一种新的半乳糖血症以来，已经有35年多的时间了。虽然人类GALM基因（及其相应的蛋白质）已经被发现十多年了，但它以前没有与半乳糖血症相关。Wada及其同事现在已经最终证明，GALM基因中至少有五个突变与半乳糖血症样症状有关。这些症状最像II型半乳糖血症：血液半乳糖浓度增加，而1-磷酸半乳糖水平没有变化。研究中的两名患者患有白内障。没有任何可检测到的影响肝脏或胃肠道系统的症状。由于所有这些患者目前都是儿童，GALM缺乏症的长期成人后果仍然未知。遗传变化导致点突变，引入终止密码子或引起GALM中的氨基酸变化，或引起过早终止的移码。蛋白质序列中的两个变化发生在相距甚远的点（p.G142R和p.R267G）。受影响的残基都不构成活性位点的一部分，作者认为它们的作用是由于蛋白质整体结构的细微改变和/或这种结构的不稳定性。这两种假设都可以解释细胞提取物中GALM活性的丧失
This Commentary explores some of the implications of the recent discovery of a novel form of galactosemia. This disease has been recognized since 1908. During the twentieth century, the molecular basis of galactosemia was revealed through two parallel lines of inquiry. First, the pioneering work of Leloir and colleagues elucidated the pathway by which the monosaccharide galactose is metabolized. Second, various genetic studies established that galactosemia is an inherited metabolic disease. Galactose cannot enter the glycolytic pathway directly. To be metabolized it is converted to glucose 6-phosphate in four enzyme-catalyzed steps. First, the sugar is phosphorylated at the expense of adenosine triphosphate (ATP) in a reaction catalyzed by galactokinase (GALK1). The resulting galactose 1-phosphate reacts with UDP-glucose producing glucose 1-phosphate and UDP-galactose. This reaction is catalyzed by galactose 1-phosphate uridylyltransferase (GALT). UDPgalactose 4’-epimerase (GALE) enables the regeneration of UDP-glucose by catalyzing the isomerization of UDPgalactose. A second isomerization reaction (catalyzed by phosphoglucomutase, PGM) converts glucose 1-phosphate to the glycolytic intermediate glucose 6-phosphate. The reactions catalyzed by GALK1, GALT, and GALE are the core reactions of the Leloir pathway. GALK1 is highly siteand stereo-specific. It acts only on the α-anomer of D-galactose producing α-D-galactose 1-phosphate. However, in solution, galactose exists in equilibrium between the αand β-anomers. Although the two anomers do interconvert in aqueous solution, the rate of utilization of α-D-galactose can exceed its rate of generation. Galactose mutarotase (aldose 1-epimerase, GALM) catalyzes this reaction with impressive turnover numbers (12,000 s for the human enzyme). This ensures that the Leloir pathway is supplied with sufficient amounts of α-D-galactose. In 1956, it was demonstrated that galactosemia can be associated with inherited mutations in the GALT gene. While this is the most common form of the disease, mutations in genes encoding other enzymes in the Leloir pathway can also cause galactosemia. Thus, GALT deficiency has become known as classical galactosemia or type I galactosemia (OMIM 230400). Type II galactosemia (OMIM 230200; discovered in 1967) results from mutations in the GALK1 gene. In 1981, type III galactosemia, or GALE deficiency (OMIM 230350) was discovered. Galactosemia has a very wide spectrum of symptoms ranging from almost no phenotype to life-threatening metabolic disturbances. The most severe forms, even if treated by the removal of galactose and its precursors from the diet, almost always result in severe physical disability and cognitive impairment. This variation results primarily from the large number of mutations that can cause the disease—over 300 are currently known. Typically, mutations in GALT are associated with more severe forms of the disease that manifest early in childhood and result in liver, brain, and ovarian damage. In contrast, type II galactosemia is associated with much milder consequences of which earlyonset cataracts is the most common. Type III galactosemia probably has the widest range of symptoms. The mildest forms are almost asymptomatic, whereas the most severe have similar symptoms to type I. It has been more than 35 years since a new form of galactosemia has been discovered. While the human GALM gene (and its corresponding protein) have been known for over a decade, it has not previously been associated with galactosemia. Wada and coworkers have now conclusively demonstrated that at least five mutations in the GALM gene are associated with galactosemia-like symptoms. These symptoms are most like type II galactosemia: increased blood galactose concentrations with no change in the levels of galactose 1-phosphate. Two of the patients studied had developed cataracts. None had any detectable symptoms affecting the liver or gastrointestinal system. Because all these patients are currently children, the long-term, adult consequences of GALM deficiency remain unknown. The genetic changes result in point mutations that introduce stop codons or cause amino acid changes in GALM, or frameshifts that cause premature termination. The two changes in the protein sequence occur at widely separated points (p.G142R and p.R267G). Neither of the affected residues forms part of the active site and the authors suggest that their effects result from subtle alterations to the protein’s overall structure and/ or destablization of this structure. Both hypotheses would explain the observed loss of GALM activity in cell extracts
影响因子：
3.5
作者：
Ai, YJ;Zheng, Z;Stambolian, D
通讯作者：
Stambolian, D