Abstract
In animals, the main precursor for glycosaminoglycan and furthermore proteoglycan biosynthesis, like hyaluronic acid, is UDP-glucuronic acid, which is synthesized via the nucleotide sugar oxidation pathway. Mutations in this pathway cause severe developmental defects (deficiency in the initiation of heart valve formation). In plants, UDP-glucuronic acid is synthesized via two independent pathways. Beside the nucleotide sugar oxidation pathway, a second minor route to UDP-glucuronic acid exist termed the myo-inositol oxygenation pathway. Within this myo-inositol is ring cleaved into glucuronic acid, which is subsequently converted to UDP-glucuronic acid by glucuronokinase and UDP-sugar pyrophosphorylase. Here we report on a similar, but bifunctional enzyme from zebrafish (Danio rerio) which has glucuronokinase/putative pyrophosphorylase activity. The enzyme can convert glucuronic acid into UDP-glucuronic acid, required for completion of the alternative pathway to UDP-glucuronic acid via myo-inositol and thus establishes a so far unknown second route to UDP-glucuronic acid in animals. Glucuronokinase from zebrafish is a member of the GHMP-kinase superfamily having unique substrate specificity for glucuronic acid with a Km of 31±8 µM and accepting ATP as the only phosphate donor (Km: 59±9 µM). UDP-glucuronic acid pyrophosphorylase from zebrafish has homology to bacterial nucleotidyltransferases and requires UTP as nucleosid diphosphate donor. Genes for bifunctional glucuronokinase and putative UDP-glucuronic acid pyrophosphorylase are conserved among some groups of lower animals, including fishes, frogs, tunicates, and polychaeta, but are absent from mammals. The existence of a second pathway for UDP-glucuronic acid biosynthesis in zebrafish likely explains some previous contradictory finding in jekyll/ugdh zebrafish developmental mutants, which showed residual glycosaminoglycans and proteoglycans in knockout mutants of UDP-glucose dehydrogenase.
Highlights
The skeleton of vertebrates provides structural support for muscle attachments and a protection of internal organs [1]
Glycosaminoglycan (GAG) and proteoglycan (PG) biosynthesis requires UDP-glucuronic acid (UDP-GlcA) as a common carbohydrate precursor found in hyaluronic acid, chondroitin, dermatan and heparin
Skeletal development can be disrupted by mutations at several steps in the pathway of GAG and PG biosynthesis [1]. jekyll/ugdh zebrafish mutants with diminished UDP-glucose dehydrogenase (UGDH) activity show defective craniofacial and coronary development. jekyll/ugdh zebrafish mutants are deficient in the initiation of heart valve formation [7,8]
Summary
The skeleton of vertebrates provides structural support for muscle attachments and a protection of internal organs [1] These functions rely on the coordinated secretion of extracellular matrix (ECM) by skeletal precursor cells during embryonic development [1]. As UDP-xylose synthase uses UDPGlcA as a substrate to form UDP-xylose after decarboxylation, one would expect very similar staining patterns in both mutants, because the enzyme UGDH is upstream of the uxs mutant. One explanation for this incongruity could be that another protein/ pathway from zebrafish partially compensates for the lack of UGDH [8]
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