Kjellén L
Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, SE-751 23 Uppsala, Sweden.
Biochem Soc Trans. 2003 Apr;31(2):340-2. doi: 10.1042/bst0310340.
During the biosynthesis of heparan sulphate (HS) in the Golgi compartment, the first modification enzyme, glucosaminyl N-deacetylase/N-sulphotransferase (NDST), starts to work on the growing HS polysaccharide chain. This enzyme defines the overall design of the sulphation pattern, which will determine the ability of the HS chain to interact with target molecules. NDST removes acetyl groups from glucosamine residues and replaces them with sulphate groups. These N-sulphate groups are essential for further modification during biosynthesis; without N-sulphation, no O-sulphation or conversion of glucuronic acid into iduronic acid will occur. Four NDST isoforms, transcribed from four genes, have been identified. Much of our work is concentrated on how the enzymes are organized within the Golgi compartment and the identification of interacting partners. In addition, we study mice in which the gene encoding NDST-1 or NDST-2 has been knocked out. NDST-1 knockout mice with altered HS structure die at birth due to lung failure, whereas lack of NDST-2 results in abnormal mast cells. Since NDSTs have a key role in HS design (see above), these mice can be used to study HS function. Areas of interest are cell differentiation, growth, inflammation, cancer, lipid metabolism and microbial infection.
在高尔基体区室中硫酸乙酰肝素（HS）的生物合成过程中，第一种修饰酶，即氨基葡萄糖N-脱乙酰酶/N-磺基转移酶（NDST），开始作用于不断增长的HS多糖链。这种酶决定了硫酸化模式的整体设计，而硫酸化模式将决定HS链与靶分子相互作用的能力。NDST从氨基葡萄糖残基上去除乙酰基，并用硫酸基团取代它们。这些N-硫酸基团对于生物合成过程中的进一步修饰至关重要；没有N-硫酸化，就不会发生O-硫酸化或葡萄糖醛酸向艾杜糖醛酸的转化。已鉴定出由四个基因转录产生的四种NDST同工型。我们的许多工作集中在这些酶在高尔基体区室中的组织方式以及相互作用伙伴的鉴定上。此外，我们还研究编码NDST-1或NDST-2的基因被敲除的小鼠。HS结构改变的NDST-1基因敲除小鼠因肺功能衰竭在出生时死亡，而缺乏NDST-2则导致肥大细胞异常。由于NDST在HS设计中起关键作用（见上文），这些小鼠可用于研究HS的功能。感兴趣的领域包括细胞分化、生长、炎症、癌症、脂质代谢和微生物感染。
