"this gene looks like something most people call COG1559, but we doubt that it has the same function as most of the other genes called COG1559. In any event, we do not know what the function is, just as we do not know what the function of the other genes called COG1559."
The level of co-occurrence of these four genes makes it extremely
likely that they are functionally related.
The DNA polymerase III, delta' subunit is part of the clamp
loading and unloading machinery (see the
2006 paper by Neuwald for
a summary).
The Thymidylate kinase (EC 2.7.4.9) is used to phosphorylate
dTMP to dTDP or dUMP to dUDP. I do not see the connection to the
DNA polymerase. However, I do think that it might be worth noting
that the genome of the Acidianus virus contains 57 genes. In
a recent paper paper by
Peng, Basta, Häring, Garrett, and Prangishvili the authors note:
"Of the 57 predicted ORFs, only three produced significant matches in public sequence databases with genes encoding a glycosyltransferase, a thymidylate kinase and a protein-primed DNA polymerase."
Ross, I read thru your write-up about clustering of PA2961 and around. A few quick comments: I. On connection with DNA replication: 1. In my opinion, the connection of DNA polymerase III and Thymidylate kinase (EC 2.7.4.9) is totally straightforward. The latter is involved in supplying (via synthesis and recylcing) of building blocks. If you look even at: http://www.genome.ad.jp/dbget-bin/show_pathway?rn00240+R02094 You will see that this reaction (ATP + dTMP <=> ADP + dTDP) is ultimately leading to formation of dTTP that goes straight to DNA synthesis (hence your DNA polymerase). (The next step being: nucleoside-diphosphate kinase (EC 2.7.4.6) ATP + dTDP = ADP + dTTP And the previous step: thymidine kinase (EC 2.7.1.21 ) ATP + thymidine = ADP + dTMP 2. The connection with viruses and phages is very insightful and noncoincidential. Art some point (~ 1 year ago) with Rob we did a quick stats of which bacterial genes/subsystems often occur in phage. It was driven by NAD story, but nonetheless, DNA replication SS was a clear champion on phages (just by “counts” of phage genome connectiosn to any given SS): Subsystem Counts DNA-replication 171 Ribonucleotide_reduction 62 DNA_Repair_Base_Excision 52 Prophage_lysogenic_conversion_modules 41 ... Folate_Biosynthesis 32 pyrimidine_conversions 24 As you can see from these old data, not only replication, but pyrimidine converions (home of 2.7.4.9) is VERY HIGH on the list. Moreover, not only various DNA polymersases and such, but also these two enzymes: - thymidine kinase (EC 2.7.1.21 ) and - thymidylate synthase (EC 2.1.1.45) 5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP Were among the most popular bacterial enzymes in phages (~25 instances of each). As you see both enzymes produce dTMP (!!!), am immediate precursor for 2.7.4.9 on the way to dTTP and DNA synthesis. Unfortunately in Rob;’s data I could not find phage stats for 2.7.4.9 but in some sense it doesn’t matter. Phage doesn’t have to carry ALL components of replication machinery, only those that appear limiting. Therefore if 2.7.4.9 activity of the host is high enough it may not be on the extant phages as a positively selected feature. See what I mean? That in my view tales care of DNA metabolism connections. II. On possible connections with aminochorismate and PabA-PabC: Roy is the best person to assess whether “predicted aminodeoxychorismate lyase”. I strongly doubt it, but he would know for sure. If it was real, or, putting it differently, if any liason with PabA could be inferred, the only connection I could foresee would be via folate. As you see from the previous section, Folate biosynthesis SS is high in phages, and I am sure that the connection is via folate-dependent thymidylate synthase (EC 2.1.1.45). We may try to elaborate more on that as long as we can really see a cnnection on the biochemical leve. To push further PABA connection, not that aminodeoxychorismate lyase (PA2964), one intruder between FAS cluster (see below) and DNA metabolsm cluster (with 2.7.4.9) is replaced by another intruder from the same system in Xhantomonasand Xylella (gene 22 in yoru last image, EC 6.3.5.8). That should mean something! III. On possible connections with Fatty Acid Synthesis (FAS): Well. It is FAS, all of these genes: PA2965-2969. However, I can’t make much of it. We know a lot about FAS in Pseudmonas, and tehere is no major gaps that we could use YceG to fill-in. IV. YcfH being a putative nuclease fits very nicely in the whole DNA metabolism related clustering. We may try to think of a particular role, butr that would take somebody like Dushko. Why don’t we ask him? It looks like the hwole story is gram-negative (while he is more a gram-positive guy), but he may have enough general knowledge. SUMMARY on YceG: What is the most likely functional link? In my opinion the most likely link is with DNA replication machinery in a broader sense (including supply if building blocks). The exact function – no clue. The second option and not unrelated is a connection with PABA synthesis (as goes to folate, and relates to DNA via Thymidilate among other things. FAS seems the least likely connection. Finally, I enclose an old paper that has a discussion of this cluster in Xhanthomonas (abstract below). Check it out. Does it help at all? AO. FEMS Microbiol Lett. 2000 Dec 1;193(1):129-36. Characterization of the acyl carrier protein gene and the fab gene locus in Xanthomonas albilineans. Huang G, Zhang L, Birch RG. Department of Botany, The University of Queensland, Brisbane, Qld., Australia. A genomic region containing the fatty acid biosynthetic (fab) genes was isolated from the sugarcane leaf-scald pathogen Xanthomonas albilineans. The order and predicted products of fabG (beta-ketoacyl reductase), acpP (acyl carrier protein), fabF (ketoacyl synthase II) and downstream genes in X. albilineans are very similar to those in Escherichia coli, with one exception. Sequence analysis, confirmed by insertional knockout and specific substrate feeding experiments, shows that the position occupied by pabC (encoding aminodeoxychorismate lyase) in other bacteria is occupied instead by pabB (encoding aminodeoxychorismate synthase component I) in X. albilineans. Downstream of pabB, X. albilineans resumes the arrangement common to characterized Gram-negative bacteria, with three transcriptionally coupled genes, encoding an ORF340 protein of undefined function, thymidylate kinase and delta' subunit of DNA polymerase III holoenzyme (HolB). Different species may obtain a common advantage from coordinated regulation of the same biosynthetic pathways using different genes in this region. PMID: 11094291