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TitleStructural and Functional Analysis of Heparosan Synthase 2 from (PmHS2) to Improve the Synthesis of Heparin.
Journal, issue, pagesACS Catal, Vol. 14, Issue 9, Page 6577-6588, Year 2024
Publish dateMay 3, 2024
AuthorsEduardo Stancanelli / Juno A Krahn / Elizabeth Viverette / Robert Dutcher / Vijayakanth Pagadala / Mario J Borgnia / Jian Liu / Lars C Pedersen /
PubMed AbstractHeparin is a widely used drug to treat thrombotic disorders in hospitals. Heparosan synthase 2 from (PmHS2) is a key enzyme used for the chemoenzymatic synthesis of heparin oligosaccharides. It has ...Heparin is a widely used drug to treat thrombotic disorders in hospitals. Heparosan synthase 2 from (PmHS2) is a key enzyme used for the chemoenzymatic synthesis of heparin oligosaccharides. It has both activities: glucosaminyl transferase activity and glucuronyl transferase activity; however, the mechanism to carry out the glyco-oligomerization is unknown. Here, we report crystal structures of PmHS2 constructs with bound uridine diphosphate (UDP) and a cryo-EM structure of PmHS2 in complex with UDP and a heptasaccharide (NS 7-mer) substrate. Using a LC-MC analytical method, we discovered the enzyme displays both a two-step concerted oligomerization mode and a distributive oligomerization mode depending on the non-reducing end of the starting oligosaccharide primer. Removal of 7 amino acid residues from the C-terminus results in an enzymatically active monomer instead of dimer and loses the concerted oligomerization mode of activity. In addition, the monomer construct can transfer N-acetyl glucosamine at a substrate concentration that is ∼7-fold higher than wildtype enzyme. It was also determined that an F529A mutant can transfer an N-sulfo glucosamine (GlcNS) saccharide from a previously inactive UDP-GlcNS donor. Performing the glyco-transfer reaction at a high substrate concentration and the capability of using unnatural donors are desirable to simplify the chemoenzymatic synthesis to prepare heparin-based therapeutics.
External linksACS Catal / PubMed:39990868 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.982 - 3.3 Å
Structure data

43269

8viw

EMDB-43269, PDB-8viw:
Cryo-EM structure of heparosan synthase 2 from Pasteurella multocida with polysaccharide in the GlcNAc-T active site
Method: EM (single particle) / Resolution: 3.3 Å

PDB-8vh7:
Crystal structure of heparosan synthase 2 from Pasteurella multocida at 1.98 A
Method: X-RAY DIFFRACTION / Resolution: 1.982 Å

PDB-8vh8:
Crystal structure of heparosan synthase 2 from Pasteurella multocida at 2.85 A
Method: X-RAY DIFFRACTION / Resolution: 2.85 Å

Chemicals

ChemComp-MN:
Unknown entry

ChemComp-UDP:
URIDINE-5'-DIPHOSPHATE / UDP*YM

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-CL:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • pasteurella multocida (bacteria)
KeywordsTRANSFERASE / glycosyltransferase / heparosan / chemoenzymatic synthesis / heparan sulfate / polysaccharide synthase / complex

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