Document Detail


The Gd(3+) complex of a fatty acid analogue of DOTP binds to multiple albumin sites with variable water relaxivities.
MedLine Citation:
PMID:  11735466     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The 20 MHz water relaxivity (r(1)) of gadolinium(III) complexes formed with two fatty acid analogues of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) were shown to increase substantially in the presence of albumin. The r(1) values of Gd(C(8)-DOTP)(5-) and Gd(C(11)-DOTP)(5-) in water were similar to that of the parent GdDOTP(5-), a q = 0 complex known to relax water very efficiently via an outer-sphere mechanism. Neither fatty acid analogue formed apparent aggregates or micelles in water up to 20 mM, but both showed dramatic increases in r(1) upon addition of albumin. Further ultrafiltration studies of Gd(C(11)-DOTP)(5-) in the presence of non-defatted HSA showed that the complex binds at a minimum of five high-affinity fatty acid sites with stepwise binding constants ranging from 1.27 x 10(5) to 2.7 x 10(3) M(-1). The 20 MHz relaxivity of Gd(C(11)-DOTP)(5-) in the presence of excess HSA was 23 mM(-1) s(-1) at 25 degrees C. The NMRD curve showed a broad maximum 20-30 MHz which fitted well to standard theory for a q = 0 complex with rapid outer-sphere water exchange. The r(1b) of Gd(C(11)-DOTP)(5-) bound at the tightest site on HSA was approximately 40 mM(-1) s(-1) at 5 degrees C, an extraordinarily high value for an outer-sphere complex. However, the r(1b) of Gd(C(11)-DOTP)(5-) bound at the weaker sites on HSA was considerably lower, approaching the relaxivity of the free complex in water. This suggests that the complex bound in the highest affinity fatty acid site is less mobile than the same complex bound at the weaker affinity fatty acid sites. This combined ultrafiltration and relaxivity study demonstrates that the common assumption of a single r(1b) value for a Gd(3+) complex bound at several protein sites is not a valid approximation.
Authors:
P Caravan; M T Greenfield; X Li; A D Sherry
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Inorganic chemistry     Volume:  40     ISSN:  0020-1669     ISO Abbreviation:  Inorg Chem     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-12-12     Completed Date:  2002-02-05     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0366543     Medline TA:  Inorg Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6580-7     Citation Subset:  IM    
Affiliation:
EPIX Medical, 71 Rogers Street, Cambridge, Massachusetts 02142, USA.
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MeSH Terms
Descriptor/Qualifier:
Algorithms
Binding Sites
Chemistry, Physical
Dansyl Compounds / chemistry
Fatty Acids / chemistry*,  metabolism
Fluorescence
Gadolinium / chemistry*
Humans
Ligands
Models, Molecular
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
Organometallic Compounds / chemical synthesis*,  chemistry
Organophosphorus Compounds / chemistry*
Phosphonic Acids / chemical synthesis,  chemistry
Physicochemical Phenomena
Proteins / chemistry
Sarcosine / analogs & derivatives*,  chemistry
Serum Albumin / chemistry,  metabolism
Water / chemistry,  physiology
Grant Support
ID/Acronym/Agency:
CA-84697/CA/NCI NIH HHS; RR-02584/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/1-(1-octyl-methyl-phosphonic acid)-4,7,10-tris(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane; 0/1-(1-undecyl-methyl-phosphonic acid)-4,7,10-tris(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane; 0/Dansyl Compounds; 0/Fatty Acids; 0/Ligands; 0/Organometallic Compounds; 0/Organophosphorus Compounds; 0/Phosphonic Acids; 0/Proteins; 0/Serum Albumin; 107-97-1/Sarcosine; 1093-96-5/dansylsarcosine; 7440-54-2/Gadolinium; 7732-18-5/Water; 91987-74-5/1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)

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


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