Hyaluronan Synthases

Abstract

In 1934, Meyer and Palmer isolated a novel, high M r glycosaminoglycan from the vitreous of the eye (1). They showed that this substance contained a hexuronic acid, an amino sugar, and no sulfoesters and proposed the name hyaluronic acid (hyaluronan, HA), 1 from the Greek hyaloid (vitreous) and uronic acid. It took 20 years before Weissmann and Meyer (2) finally established the precise structure of the repeating disaccharide unit of hyaluronic acid (GlcA␤(133)GlcNAc␤ (134)). The number of repeating disaccharides in an HA molecule can exceed 30,000, a M r Ͼ10 7 . MedLine surveys for reports describing the structure, synthesis, degradation, and biology of HA reveal a steadily increasing interest in this biopolymer during the four decades following the determination of its structure: 790 papers published from 1966 to 1975; 2200 from 1976 to 1985; over 3300 from 1986 to 1996. During this time, HA has been identified in virtually every tissue in vertebrates and has achieved widespread use in various clinical applications, most notably and appropriately as an intra-articular matrix supplement (3) and in eye surgery. This period has also seen a transition from the original perception that HA is primarily a passive structural component in the matrix of a few connective tissues and in the capsule of certain strains of bacteria to a recognition that this ubiquitous macromolecule is dynamically involved in many biological processes: from modulating cell migration and differentiation during embryogenesis (4) to regulation of extracellular matrix organization and metabolism (5) to important roles in the complex processes of metastasis, wound healing, and inflammation (6, 7). Further, it is becoming clear that HA is highly metabolically active and that cells focus much attention on the processes of its synthesis and catabolism. For example, the half-life of HA in tissues ranges from 1 to 3 weeks in cartilage (8) to Ͻ1 day in epidermis (9). In this report, we describe recent advances that provide exciting new insights into the biosynthetic side of these metabolic processes. HA BiosynthesisIt is now clear that a single protein utilizes both sugar substrates to synthesize HA (10). The abbreviation HAS, for the HA synthase, has gained widespread support for designating this class of enzymes and should now be accepted as standard nomenclature. Markovitz et al. (11) successfully characterized the HAS activity from Streptococcus pyogenes and discovered the enzyme's membrane localization and its requirements for sugar nucleotide precursors and Mg 2ϩ. Prehm (12) found that elongating HA, made by B6 cells, was digested by hyaluronidase added to the medium and proposed that HAS resides at the plasma membrane. Philipson and Schwartz (13) also showed that HAS activity cofractionated with plasma membrane markers in mouse oligodendroglioma cells. HAS assembles high M r HA that is simultaneously extruded through the membrane into the extracellular space (or to make the cell capsule in the case of bacteria) as glycosaminoglycan synthesis ...

Selective proliferation of rat hepatocyte progenitor cells in serum-free culture

“…Such diversity results from the large number of hyaluronan-binding proteins (termed hyaladherins), which exhibit significant differences in their tissue expression, cellular localization, specificity, affinity and regulation. Three HA synthase (HAS) genes, coding for HAS-1, 2 and 3, are recognized to synthesize HA 8 . HAS is located at the inner cell membrane, where the newly synthesized HA is extruded into the extracellular space 9 .…”

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

“…Three mammalian HAS genes have been cloned, designated HAS-1, HAS-2 and HAS-3 [13]. These three genes display sequence homology and share common exon-intron boundaries between exons 2 and 3 [14], yet, they are localized on separate chromosomes [15].…”

Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors

“…Three hyaluronan synthase genes (Has1, Has2 and Has3) have been identified and characterized in vertebrates, 11,12 and has been shown to have different expression patterns. 13 They are plasma membrane proteins capable of hyaluronan polymerization, and may interact with different cytoplasmic proteins with potential regulatory roles in hyaluronan biosynthesis.…”