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Identification of Key Residues Determining Species Differences in Inhibitor Binding of Microsomal Prostaglandin E Synthase-1[S]

Pawelzik, Sven-Christian ; Uda, Narasimha Rao ; Spahiu, Linda ; Jegerschöld, Caroline ; Stenberg, Patric ; Hebert, Hans ; Morgenstern, Ralf ; Jakobsson, Per-Johan

The Journal of biological chemistry, 2010-09, Vol.285 (38), p.29254-29261 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Identification of Key Residues Determining Species Differences in Inhibitor Binding of Microsomal Prostaglandin E Synthase-1[S]
Autor: Pawelzik, Sven-Christian ; Uda, Narasimha Rao ; Spahiu, Linda ; Jegerschöld, Caroline ; Stenberg, Patric ; Hebert, Hans ; Morgenstern, Ralf ; Jakobsson, Per-Johan
Assuntos: Active site ; Amino Acid Sequence ; Animals ; Basal levels ; Binding Sites ; Bioengineering ; Bioteknik ; Chimeric Protein ; Conventional drugs ; Cyclooxygenases ; Drug products ; Enzyme inhibition ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Enzyme Mechanisms ; Enzyme Mutation ; Enzymology ; Humans ; Immunoblotting ; Inflammation ; Inflammatory reaction ; Inhibitor activity ; Inhibitor-binding Site ; Inhibitory Concentration 50 ; Intramolecular Oxidoreductases - antagonists & inhibitors ; Intramolecular Oxidoreductases - chemistry ; Intramolecular Oxidoreductases - genetics ; Intramolecular Oxidoreductases - metabolism ; Medicin och hälsovetenskap ; Membrane Proteins ; Microsomal prostaglandin ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; mPGES-1 ; MPGES1 Inhibitor ; Mutagenesis, Site-Directed ; Natural substrates ; Non-steroidal anti-inflammatory drugs ; Nonsteroidal Anti-inflammatory Drugs (NSAIDs) ; Phospholipid bilayer ; Phospholipids ; Proinflammatory cytokines ; Prostaglandin E2 (PGE2) ; Prostaglandin-E Synthases ; Prostaglandine ; Prostaglandins ; Protein Binding ; Protein Structure and Folding ; Protein Structure, Secondary ; Rats ; Sequence Homology, Amino Acid ; Synthases ; TECHNOLOGY ; TEKNIKVETENSKAP ; Transmembrane helices
É parte de: The Journal of biological chemistry, 2010-09, Vol.285 (38), p.29254-29261
Descrição: Microsomal prostaglandin E synthase-1 (MPGES1) is induced during an inflammatory reaction from low basal levels by pro-inflammatory cytokines and subsequently involved in the production of the important mediator of inflammation, prostaglandin E2. Nonsteroidal anti-inflammatory drugs prevent prostaglandin E2 production by inhibiting the upstream enzymes cyclooxygenases 1 and 2. In contrast to these conventional drugs, a new generation of NSAIDs targets the terminal enzyme MPGES1. Some of these compounds potently inhibit human MPGES1 but do not have an effect on the rat orthologue. We investigated this interspecies difference in a rat/human chimeric form of the enzyme as well as in several mutants and identified key residues Thr-131, Leu-135, and Ala-138 in human MPGES1, which play a crucial role as gate keepers for the active site of MPGES1. These residues are situated in transmembrane helix 4, lining the entrance to the cleft between two subunits in the protein trimer, and regulate access of the inhibitor in the rat enzyme. Exchange toward the human residues in rat MPGES1 was accompanied with a gain of inhibitor activity, whereas exchange in human MPGES1 toward the residues found in rat abrogated inhibitor activity. Our data give evidence for the location of the active site at the interface between subunits in the homotrimeric enzyme and suggest a model of how the natural substrate PGH2, or competitive inhibitors of MPGES1, enter the active site via the phospholipid bilayer of the membrane.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Identification of Key Residues Determining Species Differences in Inhibitor Binding of Microsomal Prostaglandin E Synthase-1[S]

Pawelzik, Sven-Christian ; Uda, Narasimha Rao ; Spahiu, Linda ; Jegerschöld, Caroline ; Stenberg, Patric ; Hebert, Hans ; Morgenstern, Ralf ; Jakobsson, Per-Johan

United States: Elsevier Inc

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