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dc.contributor.author
Pierdominici Sottile, Gustavo
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dc.contributor.author
Cossio Pérez, Rodrigo
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dc.contributor.author
Da Fonseca, Isabel
dc.contributor.author
Kizjakina, Karina
dc.contributor.author
Tanner, John J.
dc.contributor.author
Sobrado, Pablo
dc.date.available
2020-03-18T20:40:34Z
dc.date.issued
2018-07
dc.identifier.citation
Pierdominici Sottile, Gustavo; Cossio Pérez, Rodrigo; Da Fonseca, Isabel; Kizjakina, Karina; Tanner, John J.; et al.; Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase; American Chemical Society; Biochemistry; 57; 26; 7-2018; 3713-3721
dc.identifier.issn
0006-2960
dc.identifier.uri
http://hdl.handle.net/11336/100129
dc.description.abstract
Galactose is an abundant monosaccharide found exclusively in mammals as galactopyranose (Galp), the six-membered ring form of this sugar. In contrast, galactose appears in many pathogenic microorganisms as the five-membered ring form, galactofuranose (Galf). Galf biosynthesis begins with the conversion of UDP-Galp to UDP-Galf catalyzed by the flavoenzyme UDP-galactopyranose mutase (UGM). Because UGM is essential for the survival and proliferation of several pathogens, there is interest in understanding the catalytic mechanism to aid inhibitor development. Herein, we have used kinetic measurements and molecular dynamics simulations to explore the features of UGM that control the rate-limiting step (RLS). We show that UGM from the pathogenic fungus Aspergillus fumigatus also catalyzes the isomerization of UDP-arabinopyranose (UDP-Arap), which differs from UDP-Galp by lacking a -CH 2 -OH substituent at the C5 position of the hexose ring. Unexpectedly, the RLS changed from a chemical step for the natural substrate to product release with UDP-Arap. This result implicated residues that contact the -CH 2 -OH of UDP-Galp in controlling the mechanistic path. The mutation of one of these residues, Trp315, to Ala changed the RLS of the natural substrate to product release, similar to the wild-type enzyme with UDP-Arap. Molecular dynamics simulations suggest that steric complementarity in the Michaelis complex is responsible for this distinct behavior. These results provide new insight into the UGM mechanism and, more generally, how steric factors in the enzyme active site control the free energy barriers along the reaction path.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Aspergillus fumigatus
dc.subject
UDP-galactopyranose mutase
dc.subject
Molecular dynamics
dc.subject
UGM
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-03-11T13:02:05Z
dc.journal.volume
57
dc.journal.number
26
dc.journal.pagination
3713-3721
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Pierdominici Sottile, Gustavo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Cossio Pérez, Rodrigo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Da Fonseca, Isabel. Virginia Polytechnic Institute And State University; Estados Unidos
dc.description.fil
Fil: Kizjakina, Karina. Virginia Polytechnic Institute And State University; Estados Unidos
dc.description.fil
Fil: Tanner, John J.. University of Missouri; Estados Unidos
dc.description.fil
Fil: Sobrado, Pablo. Virginia Polytechnic Institute And State University; Estados Unidos
dc.journal.title
Biochemistry
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.biochem.8b00323
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492245/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acs.biochem.8b00323
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