Irina Shevyreva (Bochum / DE), Lena Sophie Fritsch (Bochum / DE), Leander Mika Koch (Bochum / DE), Anton Effing (Bochum / DE), Meriyem Aktas (Bochum / DE), Franz Narberhaus (Bochum / DE)
Phosphatidylcholine (PC), a typical eukaryotic phospholipid, is an important lipid in some bacteria as well. The amount of PC in bacteria ranges from a few percent of total membrane lipids in Xanthomonas campestris to nearly 70% in Acetobacter aceti. Notably, in certain pathogenic or symbiotic bacteria, PC plays a crucial role in facilitating interactions with their eukaryotic hosts.
One of the most common PC biosynthesis pathways in bacteria is a three-step S-adenosylmethionine (SAM)-dependent methylation of phosphatidylethanolamine (PE) to PC mediated by a single or a combination of multiple phospholipid N-methyltransferases (Pmts). Pmts are classified based on their sequence similarities into the Sinorhizobium (S) and Rhodobacter (R) types. These enzymes display different substrate preferences regardless of their type. For instance, the S-type Agrobacterium tumefaciens PmtA (AtPmtA) catalyzes all three methylations of PE to produce PC, while another S-type enzyme, Rhizobium leguminosarum PmtS1, only catalyzes the first methylation step. Although AtPmtA has been extensively studied biochemically, and recent structural insights have been gained about an R-type representative from Rubellimicrobium thermophilum (RtPmtA), we still lack information about the catalytic mechanism and structural details of S-type Pmts.
The main goal of this project is the elucidation and comparative analysis of catalytic mechanisms of S-type and R-type Pmts by a combination of computational and biochemical research. Despite the low amino acid sequence identity, the two Pmt classes exhibit similar reaction mechanisms based on "proximity and desolvation". However, the number and localization of the key tyrosine residues, essential for activity, vary between the two Pmt types. RtPmtA features two highly conserved tyrosines in the binding pocket, located in the N-terminal αA-helix. In contrast, in the S-type AtPmtA, only one tyrosine, positioned in the protein core, has an impact on the enzyme´s function. This data suggests that while the basic catalytic mechanism is conserved, the specific structural features in the active site of these Pmt types reflect their evolutionary divergence.
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