Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation

精氨琥珀酸合成酶 基质(水族馆) 体外 化学 生物化学 生物 遗传学 内分泌学 内科学 分子生物学 医学 精氨酸 精氨酸酶 生态学 氨基酸
作者
Carmen Dı́ez-Fernández,Olivia Wellauer,Claudio Gemperle,Véronique Rüfenacht,Ralph Fingerhut,Johannes Häberle
出处
期刊:Journal of Medical Genetics [BMJ]
卷期号:53 (10): 710-719 被引量:11
标识
DOI:10.1136/jmedgenet-2016-103937
摘要

Citrullinemia type 1 is an autosomal-recessive urea cycle disorder caused by mutations in the ASS1 gene and characterised by increased plasma citrulline concentrations. Of the ∼90 argininosuccinate synthetase (ASS) missense mutations reported, 21 map near the substrate (aspartate or citrulline) binding site, and thus are potential kinetic mutations whose decreased activities could be amenable to substrate supplementation. This article aims at characterising these 21 ASS mutations to prove their disease-causing role and to test substrate supplementation as a novel therapeutic approach.We used an Escherichia coli expression system to study all potentially kinetic ASS mutations. All mutant enzymes were nickel-affinity purified, their activity and kinetic parameters were measured using tandem mass spectrometry and their thermal stability using differential scanning fluorimetry. Structural rationalisation of the effects of these mutations was performed.Of the characterised mutants, 13 were totally inactive while 8 exhibited decreased affinity for aspartate and citrulline. The activity of these eight kinetic mutations could be rescued to ∼10-99% of the wild-type using high l-aspartate concentrations.Substrate supplementation raised in vitro the activity of eight citrullinemia type 1 mutations with reduced affinity for aspartate. As a direct translation of these results to the clinics, we propose to further evaluate the use of oxaloacetate, a nitrogen-free aspartate precursor and already available medical food (anti-ageing and brain stimulating, not considered as a drug by the US Food and Drug Administration), in patients with citrullinemia type 1 with decreased aspartate affinity. Although only patients with kinetic mutations would benefit, oxaloacetate could offer a safe novel treatment.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
英姑应助白白采纳,获得10
刚刚
满座完成签到,获得积分10
1秒前
杨羕完成签到,获得积分10
2秒前
五六七完成签到,获得积分10
2秒前
周少完成签到,获得积分10
2秒前
兴奋的若菱完成签到 ,获得积分10
2秒前
幸福广山完成签到,获得积分10
4秒前
HMethod完成签到 ,获得积分10
6秒前
Y123完成签到,获得积分10
6秒前
7秒前
ersan完成签到,获得积分10
8秒前
Hello应助nkmenghan采纳,获得30
9秒前
9秒前
9秒前
粗心的听安完成签到,获得积分10
9秒前
念姬完成签到 ,获得积分10
10秒前
量子星尘发布了新的文献求助10
10秒前
11秒前
12秒前
指哪打哪完成签到,获得积分10
12秒前
12秒前
静静子发布了新的文献求助100
13秒前
Ray完成签到 ,获得积分10
14秒前
文静的天蓝完成签到,获得积分10
14秒前
tszjw168完成签到 ,获得积分10
15秒前
手打鱼丸完成签到 ,获得积分10
16秒前
体贴凌柏发布了新的文献求助10
16秒前
开心快乐发大财完成签到,获得积分10
18秒前
萌萌哒完成签到,获得积分10
18秒前
小龅牙吖完成签到,获得积分10
18秒前
Propitious完成签到,获得积分10
19秒前
徐先生1106完成签到,获得积分10
19秒前
Epiphany完成签到,获得积分10
20秒前
舒心的久完成签到 ,获得积分10
20秒前
闻巷雨完成签到 ,获得积分10
22秒前
北风完成签到,获得积分10
23秒前
xliiii完成签到,获得积分10
23秒前
时光倒流的鱼完成签到,获得积分10
24秒前
LL完成签到,获得积分10
24秒前
李李完成签到,获得积分20
24秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038303
求助须知:如何正确求助?哪些是违规求助? 3576013
关于积分的说明 11374210
捐赠科研通 3305780
什么是DOI,文献DOI怎么找? 1819322
邀请新用户注册赠送积分活动 892672
科研通“疑难数据库(出版商)”最低求助积分说明 815029