Document Detail


Mechanism for the transport of ammonia within carbamoyl phosphate synthetase determined by molecular dynamics simulations.
MedLine Citation:
PMID:  18220365     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Carbamoyl phosphate synthetase (CPS) is a member of the amidotransferase family of enzymes that uses the hydrolysis of glutamine as a localized source of ammonia for biosynthetic transformations. Molecular dynamics simulations for the transfer of ammonia and ammonium through a tunnel in the small subunit of CPS resulted in five successful trajectories for ammonia transfer, while ammonium was immobilized in a water pocket inside the small subunit of the heterodimeric protein. The observed molecular tunnel for ammonia transport is consistent with that suggested by earlier X-ray crystallography and site-directed mutation studies. His-353, Ser-47, and Lys-202, around the active site center in the small subunit, function cooperatively to deliver ammonia from the site of formation to the interface with the large subunit, via the exchange of hydrogen bonds with a critical water cluster within the tunnel. The NH 3 forms and breaks hydrogen bonds to Gly-292, Ser-35, Pro-358, Gly-293, and Thr-37 in a stepwise fashion "macroscopically" as it travels through the hydrophilic passage toward the subunit interface. The potential of mean force calculations along the ammonia transfer pathway indicates a low free-energy path for the translocation of ammonia with two barriers of 3.9 and 5.5 kcal/mol, respectively. These low free-energy barriers are consistent with the delivery of ammonia from the site of formation into a water reservoir toward the exit of the tunnel and migration through the hydrophilic leaving passage, respectively. The high overall free-energy barrier of 22.4 kcal/mol for the transport of ammonium additionally substantiates that the tunnel in the small subunit of CPS is not an ammonium but an ammonia channel.
Authors:
Yubo Fan; Liliya Lund; Lijiang Yang; Frank M Raushel; Yi-Qin Gao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-01-26
Journal Detail:
Title:  Biochemistry     Volume:  47     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-03     Completed Date:  2008-06-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2935-44     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA.
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MeSH Terms
Descriptor/Qualifier:
Ammonia / chemistry*,  metabolism
Binding Sites
Carbamoyl-Phosphate Synthase (Ammonia) / chemistry*,  genetics,  metabolism
Computer Simulation*
Crystallography, X-Ray
Glutamine / chemistry,  metabolism
Protein Binding
Protein Structure, Secondary
Thermodynamics
Grant Support
ID/Acronym/Agency:
R56 DK030343/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
56-85-9/Glutamine; 7664-41-7/Ammonia; EC 6.3.4.16/Carbamoyl-Phosphate Synthase (Ammonia)

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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