marinum and MAC species). Colored block arrows: blue, cysM; green, Go6983 rhomboid homologs; purple, mur1; black, rhomboid surrounding genes; white, pseudogene. White boxes indicate distances between rhomboids and upstream and downstream genes. Boxed (blue) are the species with similar arrangement for the rhomboids. Despite evolutionary differences across the genus, the Rv1337 mycobacterial orthologs shared a unique genome organization at the rhomboid locus, with many of the rhomboid surrounding genes conserved (figure 1). Typically, upstream and downstream of the rhomboid were cysM (cysteine synthetase) PF-6463922 and mur1 (glutamate racemase) encoding genes. Since Rv1337 orthologs

are almost inseparable from mur1 and cysM, it is likely that they are co-transcribed (polycistronic) or functional

selleck products partners. As such, we may consider the cluster containing mycobacterial Rv1337 orthologs as a putative operon. According to Sassetti et al [36, 37], many of the rhomboid surrounding genes are essential while others (including rhomboid protease 2, Rv1337) are required for the survival of the tubercle bacillus in macrophages [38]. Despite massive gene decay in M. leprae, ML1171 rhomboid had similar genome arrangement observed for mycobacterial species. Upstream of ML1171 were gene elements (pseudogenes) ML1168, ML1169 and ML1170 (the homolog of cysM which is conserved downstream most Rv1337 orthologs). Similar to M. lepare, the MAC species also had an ortholog of Rv1337 as

a sole rhomboid; perhaps the ortholog of Rv0110 was lost in the progenitor for MAC and M. leprae (these species are phylogenetically related and appear more ancient in comparison to M. marinum, M. ulcerans and MTC species [39]). In contrast to most mycobacterial genomes, cysM was further upstream the M. marinum rhomboid (MMAR_4059); and despite being genetically related to MTC species [40], MMAR_ 4059 does not share much of the genome organization observed for Rv1337 MTC orthologs (figure 1). The rhomboid-like element of M. ulcerans (MUL_3926, pseudogene) was identical to MMAR_4059 (~96% similarity to MMAR_4059) with a Avelestat (AZD9668) 42 bp insertion at the beginning and eight single nucleotide polymorphisms (SNPs). Perhaps the insertion disrupted the open reading frame (ORF) of MUL_3926, converting it into a pseudogene. Interestingly, MUL_3926 nearly assumed the unique organization observed for mycobacterial orthologs of Rv1337, in which the rhomboid element was upstream of mur1. The functional and evolutionary significance for the unique organization of the Rv1337 orthologs in mycobacteria is not clear. Since physiological roles are not yet ascribed to mycobacterial rhomboids, it is not certain whether MUL_3926 (psuedogene) would mimic similar roles in that it almost assumed similar genomic organization (note: functions have been ascribed to certain pseudogenes [41–43]). However, the fact that M. ulcerans is a new species (recently evolved from M.