Stern Robert
Department of Pathology, School of Medicine, 513 Parnassus Avenue, S-564, University of California San Francisco, San Francisco, CA 94143-0511, USA.
Glycobiology. 2003 Dec;13(12):105R-115R. doi: 10.1093/glycob/cwg112. Epub 2003 Sep 26.
Hyaluronan is a negatively charged, high molecular weight glycosaminoglycan found predominantly in the extracellular matrix. Intracellular locations for hyaluronan have also been documented in cytoplasm, nucleus, and nucleolus. The polymer has an extraordinarily high rate of turnover in vertebrate tissues. The focus here is to formulate a metabolic pathway for hyaluronan degradation using all available data, including the recently acquired information on the hyaluronidase gene family. Such a catabolic scheme has defied explication up to now. In somatic tissues, stepwise processing occurs, from the extracellular high molecular weight space filling, antiangiogenic approximately 107-kDa polymer, to intermediate sized highly angiogenic, inflammatory, and immune-stimulating fragments, and ultimately to tetrasaccharides that are antiapoptotic and potent inducers of heat-shock proteins. It is proposed that the high molecular weight extracellular polymer is tethered to the cell surface by the combined efforts of hyaluronan receptors and hyaluronidase-2 (Hyal-2). The hyaluronan is cleaved to a 20-kDa intermediate-sized fragment, the limit product of Hyal-2 digestion. These fragments are delivered to endosomal- and ultimately lysosomal-like structures. Further catabolism occurs there by Hyal-1, coordinated with the activity of two lysosomal beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl-glucosaminidase. A membrane-associated mini-organelle is postulated, the hyaluronasome, in which coordinated synthetic and catabolic enzyme reactions occur. The hyaluronasome can respond to the physiological states of the cell by a series of membrane-bound and soluble hyaluronan-associated receptors, binding proteins, and cofactors that trigger enzymatic events and signal transduction pathways. These in turn can be modulated by the amounts and sizes of the hyaluronan polysaccharides generated in the catabolic cascade. Most of these highly dynamic interactions remain to be determined. It is also proposed that malignant cells can commandeer some of these interactions for facilitating tumor growth and spread.
透明质酸是一种带负电荷的高分子量糖胺聚糖，主要存在于细胞外基质中。透明质酸在细胞质、细胞核和核仁中的细胞内定位也有文献记载。这种聚合物在脊椎动物组织中的更新率极高。本文的重点是利用所有可用数据，包括最近获得的关于透明质酸酶基因家族的信息，制定一条透明质酸降解的代谢途径。到目前为止，这样的分解代谢方案一直难以阐明。在体细胞组织中，会发生逐步处理过程，从细胞外高分子量的空间填充、抗血管生成的约107 kDa聚合物，到中等大小的高血管生成、炎症和免疫刺激片段，最终到具有抗凋亡作用且是热休克蛋白强效诱导剂的四糖。有人提出，高分子量的细胞外聚合物通过透明质酸受体和透明质酸酶-2（Hyal-2）的共同作用锚定在细胞表面。透明质酸被切割成20 kDa的中等大小片段，这是Hyal-2消化的极限产物。这些片段被输送到内体，最终进入类似溶酶体的结构。在那里，Hyal-1与两种溶酶体β-外切糖苷酶（β-葡萄糖醛酸酶和β-N-乙酰氨基葡萄糖苷酶）的活性协同作用，进一步发生分解代谢。推测存在一种与膜相关的微细胞器——透明质体，在其中发生协同的合成和分解代谢酶反应。透明质体可以通过一系列膜结合和可溶性透明质酸相关受体、结合蛋白和辅因子对细胞的生理状态做出反应，这些受体、蛋白和辅因子会触发酶促事件和信号转导途径。反过来，这些又可以被分解代谢级联反应中产生的透明质酸多糖的数量和大小所调节。这些高度动态的相互作用大多仍有待确定。还有人提出，恶性细胞可以利用其中一些相互作用来促进肿瘤生长和扩散。
