Novel signaling routes and molecular determinants for leukotriene biosynthesis

Romp, Erik GND

LMs derived from AA and related FAs exert diverse biological activities during inflammation. However, although discovered several decades ago, the knowledge about the regulation of the enzymes involved in LM biosynthesis remains far from completion. This thesis aimed at investigating the molecular mechanism of bacteria-induced LT formation and unveiled exotoxins secreted from pathogenic bacteria as determining factors for in cellulo 5-LOX activation. In case of S. aureus, a human commensal associated to infections of diverse severity, we identified PSMs and their receptor FPR2 as critical factors capable to induce LM biosynthesis in neutrophils. Activation of FPR2, phosphorylation of ERK1/2 as well as an increase of intracellular Ca2+ are clearly involved in PSM-mediated 5-LOX activation. Together, we here present the release of LMs and the stimulation of 5-LOX as novel biological properties of PSMs. Moreover, our findings might encourage ongoing efforts to develop alternative anti- microbial strategies focusing on exotoxin secretion, since the rise of antibiotic resistant bacteria is becoming a relevant threat to humans. In addition, we here addressed structural elements of the integral membrane protein FLAP that acts as unique helper for cellular 5-LOX product formation. Our results uncover the second cytosolic loop of FLAP as crucial domain for sufficient assembly of the LT-synthetic protein complex at the nuclear membrane. Prospective studies and the development of FLAP inhibitors should therefore consider this loop as novel binding site, since previous compounds solely target lipid-exposed domains of FLAP, resulting in highly lipophilic drugs and thus inappropriate pharmacokinetic properties. Taken together, our results significantly contribute to the expansive field of LM research and provide novel insights into the signaling and molecular determinants of LT biosynthesis upon bacterial stimulation as well as its dependency on FLAP.

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