Disease relevance of ECs3418

• Fur recently was found to regulate hmp in Salmonella typhimurium, and in Escherichia coli, the iron-chelating agent 2,2'-dipyridyl induces hmp expression [1].
• A Salmonella hmp mutant defective in flavohemoglobin (Hmp) synthesis exhibits growth that is hypersensitive to nitrosating agents [2].
• A gene, hmp, which encodes a ubiquitous protein homologous to hemoglobin was isolated among genes from Bacillus subtilis that are induced under anaerobic conditions [3].
• Overproduction of VHb-R in the hmp mutant of E. coli conferred relief from the toxicity of sodium nitroprusside, whereas VHb alone provided only partial benefit under similar condition, suggesting that the association of VHb with reductase improves its capability to relieve the deleterious effect of nitrosative stress [4].
• The hmp protein belongs to the family of two-domain flavohemoproteins, homologs of which have been isolated from various organisms such as Escherichia coli, Alcaligenes eutrophus, and Saccharomyces cerevisiae [3].

High impact information on ECs3418

• Most significantly, hmp mutants internalized by primary human peripheral monocyte-derived macrophages survived phagocytosis relatively poorly compared with similarly bound and internalized wild-type cells [2].
• That the enhanced sensitivity to macrophage microbicidal activity is due primarily to the failure of Salmonella to detoxify NO was suggested by the ability of L-N(G)-monomethyl arginine-an inhibitor of NO synthase-to eliminate the difference in killing between wild-type and hmp mutant Salmonella cells [2].
• The mutations found lie in the middle to 3' end of the dihydropteridine reductase reading frame, with the exception of one mutation which lies at codon 23, which is the only mutation found in more than one patient [5].
• SDS/PAGE has indicated a molecular mass of 44 kDa for the monomeric protein consistent with the amino-acid sequence deduced from the hmp+ gene [6].
• HB101 was used as the host for a pBR322 plasmid carrying the hmp gene [7].

Chemical compound and disease context of ECs3418

• Additionally, the hmp mutant of E. coli, carrying M. smegmatis HbN, exhibited nearly 10-fold lower cell survival under nitrosative stress and nitrite derived reactive nitrogen species as compared to the isogenic strain harboring HbN of M. tuberculosis [8].
• The haemoglobin-like protein (HMP) of E. coli previously isolated as a dihydropteridine reductase was shown to be also a ferric citrate reductase [9].
• E. coli Dihydropteridine reductase, known to have a pterin-independent oxidoreductase activity with potassium ferricyanide as electron donor, has now been shown to possess also dihydrofolate reductase activity [10].

Biological context of ECs3418

• Cellular respiration the of the hmp mutant was instantaneously inhibited in the presence of 10 microM nitric oxide (NO) but remained insensitive to NO inhibition when these cells produced VHb-R [4].
• The requirement of FNR and NarGHJI for hmp expression is completely bypassed by the addition of nitrite in the culture medium, indicating that fnr is required for transcriptional activation of narGHJI, which produces nitrite, leading to induction of hmp expression [3].
• A hmp promoter phi(hmp-lacZ)-operon fusion was constructed in the chromosome and its activity measured during the growth cycle [11].
• Putative Fnr boxes at positions -2 to +11 occur in the hmp promoter region [11].
• Anti-idiotypic antibodies elicited by pterin recognize active site epitopes in dihydrofolate reductases and dihydropteridine reductase [12].

Associations of ECs3418 with chemical compounds

• In contrast, induction of hmp was still dependent on resDE in the presence of nitrite [3].
• HB101 over expressing hmp showed increased tolerance to DETA/NO (0.5 mM) compared to WT HB101 (106% +/- 5.6% vs 67 +/- 6.2%, p <0.01) [7].
• The expression of hmp is strongly induced upon oxygen limitation, and the induction is dependent on a two-component regulatory pair, ResD and ResE, an anaerobic regulator, FNR, and respiratory nitrate reductase, NarGHJI [3].
• These data suggest that despite the absence of significant amino acid sequence homologies among the various DHFRs and DHPR, they have a fundamentally similar topography at the site of binding of the pterin moiety that is recognized by the anti-idiotypic mAbs generated by pterin [12].
• Nitrosating agents, such as S-nitrosoglutathione, deplete cellular Hcy and consequently modulate activity of the MetR regulator that binds the hmp promoter [13].

Analytical, diagnostic and therapeutic context of ECs3418

• Northern and Western blot analysis demonstrated increased flavohemoglobin expression after DETA/NO exposure and the strongest expression in HB101 carrying hmp on a multicopy plasmid [7].
• Previously characterized hmp genes from E. coli and Bacillus subtilis and the novel hmp genes from P. aeruginosa, S. typhi, C. jejuni, K. pneumoniae, and D. radiodurans were PCR amplified and introduced into a plasmid for expression in E. coli [14].

References