Proteoglycan biosynthesis

Proteoglycan (PG) synthesis is a complex mechanism that can be divided in four main steps. Core protein synthesis occurs in the rough endoplasmic reticulum (RER). Once PG core protein has been synthesized, it moves from the RER to the Golgi apparatus where the first sugar of glycosaminoalycan (GAG) chain is added on Ser residues. GAG synthesis continues by glycosyltransferases that transfer sugar moieties from UDP-sugars to GAG chains. UDP-sugars are synthesized in the cytoplasm and are translocated in the Golgi apparatus by an antiporter with UMP. Then UDP, the by-product of glycosyltransferase reactions, is hydrolyzed to UMP and phosphate by calcium activated nucleotidase 1 (CANT1). Chondroitin, dermatan and heparan sulfate synthesis starts on a Ser residue of the PG core protein with the formation of a tetrasaccharide linkage region composed of a xylose (Xyl), two galactoses (Gal) and a glucuronic acid (GlcUA). After tetrasaccharide synthesis, GAG chain elongation continues through the binding of specific saccharides defining chondroitin sulfate, dermatan sulfate and heparan sulfate. Specific enzymes are involved in this process and mutations in their gene cause different types of skeletal dysplasia (indicated in red boxes). The third step is GAG sulfation. Sulfate enters in cells through the SLC26A2 transporter and it is activated to 30-phosphoadenosine 50-phosphosulfate (PAPS) by PAPS synthase (PAPSS) in the cytosol. Through a PAPS transporter (PAPST), PAPS moves to Golgi apparatus where it is used as sulfate donor by sulfotransferases to sulfate GAGs. This reaction also produces phosphoadenosine phosphate (PAP), that is hydrolyzed into AMP and phosphate by a Golgi resident phosphoadenosine phosphate phosphatase (gPAPP). Once synthesized, PGs are secreted in extracellular space. Sulfation of GAGs is an important step in PG synthesis determining PG properties. Inorganic sulfate enters in cells through a sulfate/chloride antiporter named SLC26A2, but a small amount of sulfate could be derived from sulfur-containing amino acid metabolism. To be used by Golgi sulfotransferases, sulfate is activated to 30-phosphoadenosine 50-phosphosulfate (PAPS), the universal sulfate donor, by PAPS synthase (PAPSS2). The by-product of sulfotransferase reactions, phosphoadenosine phosphate (PAP), is hydrolyzed by a Golgi resident phosphoadenosine phosphate phosphatase (gPAPP) in order to prevent feedback inhibition of these reactions. Linked with a dotted arrow to the GeneProduct nodes are skeletal dysplasias caused by mutation in the respective gene. For further details, see [https://www.ncbi.nlm.nih.gov/pubmed/31286677].

蛋白质聚糖（PG）的合成是一个复杂的过程，可划分为四个主要步骤。核心蛋白的合成发生在粗糙内质网（RER）中。一旦蛋白质聚糖的核心蛋白合成完成，它便从RER移动至高尔基体，在那里在丝氨酸残基上添加第一个糖基化氨基糖（GAG）链的糖。GAG的合成通过糖基转移酶进行，这些酶将糖基从UDP-糖转移至GAG链。UDP-糖在细胞质中合成，并通过一种与UMP共同作用的逆向转运蛋白在高尔基体中进行转移。随后，糖基转移酶反应的副产物UDP，通过钙激活的核苷酸酶1（CANT1）水解为UMP和磷酸。软骨素、透明质酸和肝素硫酸盐的合成从蛋白质聚糖核心蛋白的丝氨酸残基开始，形成由木糖（Xyl）、两个半乳糖（Gal）和一个葡萄糖醛酸（GlcUA）组成的四糖苷键区域。四糖苷的合成完成后，GAG链的延长通过结合特定的糖苷定义软骨素硫酸盐、透明质酸硫酸盐和肝素硫酸盐。在这一过程中涉及特定的酶，其基因突变可导致不同类型的骨骼发育异常（以红色方框标注）。第三步是GAG的硫酸化。硫酸通过SLC26A2转运蛋白进入细胞，并在细胞质中由磷酸腺苷硫酸盐合成酶（PAPSS）激活为30-磷酸腺苷50-磷酸硫酸盐（PAPS）。通过PAPS转运蛋白（PAPST），PAPS移动至高尔基体，在那里作为硫酸供体被硫酸转移酶用于硫酸化GAGs。这一反应同时产生磷腺苷酸（PAP），该物质通过高尔基体 resident 磷腺苷酸磷酸酶（gPAPP）水解为AMP和磷酸，以防止这些反应的反馈抑制。一旦合成，蛋白质聚糖便分泌至细胞外空间。GAGs的硫酸化是蛋白质聚糖合成过程中的重要步骤，它决定了蛋白质聚糖的性质。无机硫酸通过名为SLC26A2的硫酸/氯离子逆向转运蛋白进入细胞，但一小部分硫酸可能源自含硫氨基酸的代谢。为了被高尔基体硫酸转移酶使用，硫酸被磷酸腺苷硫酸盐合成酶（PAPSS2）激活为通用的硫酸供体PAPS。硫酸转移酶反应的副产物磷腺苷酸（PAP）通过高尔基体 resident 磷腺苷酸磷酸酶（gPAPP）水解，以防止这些反应的反馈抑制。与基因产物节点通过虚线箭头相连的是由相应基因突变引起的骨骼发育异常。有关详细信息，请参阅[https://www.ncbi.nlm.nih.gov/pubmed/31286677]。