Common structural features of mapeg—a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism

Abstract

A novel superfamily designated MAPEG~Membrane Associated Proteins in Eicosanoid and Glutathione metabolism!, including members of widespread origin with diversified biological functions is defined according to enzymatic activities, sequence motifs, and structural properties. Two of the members are crucial for leukotriene biosynthesis, and three are cytoprotective exhibiting glutathione S-transferase and peroxidase activities. Expression of the most recently recognized member is strongly induced by p53, and may therefore play a role in apoptosis or cancer development. In spite of the different biological functions, all six proteins demonstrate common structural characteristics typical of membrane proteins. In addition, homologues are identified in plants, fungi, and bacteria, demonstrating this superfamily to be generally occurring.

GlutathioneS-Transferase Catalyzed Desulfonylation of a Sulfonylfuropyridine

“…These data and the experiments conducted with partially purified GST (from rat liver) confirmed that the formation of M1 is catalyzed by one or more GST enzymes. There are three distinct families of glutathione transferases that are localized in mitochondria, cytosol, and/or microsomes with varying substrate specificity (DeJong et al, 1988;Pickett and Lu, 1989;Jakobsson et al, 1999;Hayes et al, 2005). In the present study, the glutathione conjugation of MRL-1 appeared to be catalyzed by a microsomal GST, as formation of M1 was not observed in liver cytosolic fractions obtained from rat, dog, monkey, and human (data not shown).…”

Structural basis for induced formation of the inflammatory mediator prostaglandin E 2

“…In LTC4S an opening between helix 1 in one subunit and helix 4 in a neighboring subunit forms a V-shaped cleft that allows access to GSH from the interior of the membrane (19,20). This represents a natural entry point for labile hydrophobic substrates, such as PGH 2 and LTA 4 that, by way of membrane entry, are protected from hydrolytic degradation. In addition, PGH 2 is produced by cyclooxygenases located on the lumenal side of the endoplasmatic reticulum and diffuses through the membrane to the active site of MPGES1 located on the cytoplasmic side.…”

“…The protein is a member of the MAPEG protein family, which includes 5-lipoxygenase activating protein (FLAP), leukotriene C 4 synthase (LTC4S), microsomal glutathione transferase (MGST)1, MGST2, and MGST3 (2,3). MPGES1 is the most efficient PGES known and catalyzes the oxidoreduction of prostaglandin endoperoxide H 2 into PGE 2 with an apparent k cat /K m of 310 mM Ϫ1 s Ϫ1 [supporting information (SI) Fig.…”

“…The predominant source of PGH 2 seems derived from Cox-2, although Cox-1 may also contribute (9). Studies, mainly from disruption of the MPGES1 gene in mice, indicate key roles for MPGES1-generated PGE 2 in pathological conditions such as chronic inflammation, pain, fever, anorexia, atherosclerosis, stroke and tumorigenesis (10). Recently, a role for MPGES1 in regulating neonatal respiration was described in ref.…”

Protection Against Oxidative Stress and “IGF-I Deficiency Conditions”

“…Two of these, the cytosolic and mitochondrial GST, comprise soluble enzymes that are only distantly related [85,86]. The third family comprises microsomal GST and is now referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism [87].…”