Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Organic anion transporters (OATs) and organic cation transporters (OCTs) mediate the flux of xenobiotics across the plasma membranes of epithelia. Substrates of OATs generally carry negative charge(s) whereas substrates of OCTs are cations. The goal of this study was to determine the domains and amino acid residues essential for recognition and transport of organic anions by the rat organic anion transporter, rOAT3. An rOAT3/rOCT1 chimera containing transmembrane domains 1-5 of rOAT3 and 6-12 of rOCT1 retained the specificity of rOCT1, suggesting that residues involved in substrate recognition reside within the carboxyl-terminal half of these transporters. Mutagenesis of a conserved basic amino acid residue, arginine 454 to aspartic acid (R454D), revealed that this amino acid is required for organic anion transport. The uptakes of p-aminohippurate (PAH), estrone sulfate, and ochratoxin A were approximately 10-, approximately 48-, and approximately 32-fold enhanced in oocytes expressing rOAT3 and were only approximately 2-, approximately 6-, and approximately 5-fold enhanced for R454D. Similarly, mutagenesis of the conserved lysine 370 to alanine (K370A) suggested that K370 is important for organic anion transport. Interestingly, the charge specificity of the double mutant, R454DK370A, was reversed in comparison to rOAT3-R454DK370A preferentially transported the organic cation, MPP(+), in comparison to PAH (MPP(+) uptake/PAH uptake = 3.21 for the double mutant vs 0.037 for rOAT3). These data indicate that arginine 454 and lysine 370 are essential for the anion specificity of rOAT3. The studies provide the first insights into the molecular determinants that are critical for recognition and translocation of organic anions by a member of the organic anion transporter family.
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PMID:Arginine 454 and lysine 370 are essential for the anion specificity of the organic anion transporter, rOAT3. 1133 Oct 16

We have previously shown that the multi-functional phosphoprotein osteopontin (OPN) is present in the substantia nigra (SN) and that its mRNA and protein expression are up-regulated following toxic insult. We now report the effects of the arginine-glycine-aspartic acid (RGD)-containing peptide fragment of OPN and OPN inactivation on the survival of tyrosine hydroxylase (TH) positive neurones in primary rat ventral mesencephalic (VM) cultures and in SN in the rat. Treatment of VM cultures with the fragment of OPN containing the RGD integrin binding domain did not decrease TH positive cell number, but instead the peptide fragment protected against cell loss induced by both MPP(+) and lipopolysaccharide (LPS). Incorporation of an OPN antibody into VM cultures caused a concentration-dependent loss of TH positive neurones. The OPN antibody also exacerbated MPP(+) - and LPS-induced cell loss at all concentrations tested. In the rat, administration of the RGD-containing peptide fragment of OPN protected TH positive neurones against a mechanically-induced lesion and against 6-hydroxydopamine- and LPS-induced cell loss. The protection against 6-hydroxydopamine toxicity was confirmed in a separate study using stereological analysis. By contrast, stereotaxic injection of the OPN antibody into the SN resulted in a loss of TH positive cells. These results suggest that OPN may be necessary for the survival of TH positive cells in SN but through the RGD-containing peptide fragment may also have neuroprotective properties relevant to Parkinson's disease.
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PMID:The RGD-containing peptide fragment of osteopontin protects tyrosine hydroxylase positive cells against toxic insult in primary ventral mesencephalic cultures and in the rat substantia nigra. 2062 61