Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0348321 (Haemophilus)
 15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Haemophilus influenzae diaminopimelate epimerase was cloned, expressed, purified, and crystallized in the C2221 space group (a = 102.1 A, b = 115.4 A, c = 66.3 A, alpha = beta = gamma = 90 degrees). The three-dimensional structure was solved to 2.7 A using a single Pt derivative and the Se-Met-substituted enzyme to a conventional R factor of 19.0% (Rfree = 24.2%). The 274 amino acid enzyme consists of two structurally homologous domains, each containing eight beta-strands and two alpha-helices. Diaminopimelate epimerase is a representative of the PLP-independent amino acid racemases, for which no structure has yet been determined and substantial evidence exists supporting the role of two cysteine residues as the catalytic acid and base. Cys73 of the amino terminal domain is found in disulfide linkage, at the domain interface, with Cys217 of the carboxy terminal domain, and we suggest that these two cysteine residues in the reduced, active enzyme function as the acid and base in the mechanism.
 ...
PMID:Structural symmetry: the three-dimensional structure of Haemophilus influenzae diaminopimelate epimerase. 984 10

Diaminopimelate (DAP) epimerase (DapF) is central to the biosynthesis of both lysine and cell-wall peptidoglycan in many bacteria species. The peptidoglycan layer provides great potential for the development of novel antimicrobials as it is a uniquely prokaryotic feature. Crystals of recombinant Haemophilus influenzae DapF that diffract to beyond 2 A resolution have been obtained which facilitated the solution of the structure by molecular replacement at a resolution approximately 1 A higher than that previously determined. An analysis of the structure (i) in comparison to other PLP-independent racemaces and (ii) in relation to the catalytic mechanism and stereospecificity of DapF is presented.
 ...
PMID:Refinement of Haemophilus influenzae diaminopimelic acid epimerase (DapF) at 1.75 A resolution suggests a mechanism for stereocontrol during catalysis. 1474 37

Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.
 ...
PMID:Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry. 1503 15

In bacteria, the dehydration of 2-methylcitrate to yield 2-methylaconitate in the 2-methylcitric acid cycle is catalyzed by a cofactor-less (PrpD) enzyme or by an aconitase-like (AcnD) enzyme. Bacteria that use AcnD also require the function of the PrpF protein, whose function was previously unknown. To gain insights into the function of PrpF, the three-dimensional crystal structure of the PrpF protein from the bacterium Shewanella oneidensis was solved at 2.0 A resolution. The protein fold of PrpF is strikingly similar to those of the non-PLP-dependent diaminopimelate epimerase from Haemophilus influenzae, a putative proline racemase from Brucella melitensis, and to a recently deposited structure of a hypothetical protein from Pseudomonas aeruginosa. Results from in vitro studies show that PrpF isomerizes trans-aconitate to cis-aconitate. It is proposed that PrpF catalysis of the cis-trans isomerization proceeds through a base-catalyzed proton abstraction coupled with a rotation about C2-C3 bond of 2-methylaconitate, and that residue Lys73 is critical for PrpF function. The newly identified function of PrpF as a non-PLP-dependent isomerase, together with the fact that PrpD-containing bacteria do not require PrpF, suggest that the isomer of 2-methylaconitate that serves as a substrate of aconitase must have the same stereochemistry as that synthesized by PrpD. From this, it follows that the 2-methylaconitate isomer generated by AcnD is not a substrate of aconitase, and that PrpF is required to generate the correct isomer. As a consequence, the isomerase activity of PrpF may now be viewed as an integral part of the 2-methylcitric acid cycle.
 ...
PMID:The three-dimensional crystal structure of the PrpF protein of Shewanella oneidensis complexed with trans-aconitate: insights into its biological function. 1756 42

Diaminopimelate (DAP) epimerase catalyzes the stereoinversion of ll-DAP to meso-DAP, a precursor of l-lysine and an essential component of the bacterial peptidoglycan. This function is vital to bacteria and the enzyme therefore represents an attractive target for the design of novel anti-bacterials. DAP epimerase belongs to the group of PLP-independent amino acid racemases that function through a rather unusual mechanism involving two cysteines acting in concert as a base (thiolate) and an acid (thiol). We have solved the crystal structures of the apo-forms of DAP epimerase mutants (C73S and C217S) from Haemophilus influenzae at 2.3A and 2.2A resolution, respectively. These structures provide a snapshot of the enzyme in the first step of the catalytic cycle. Comparisons with the structures of the inhibitor-bound form reveal that the enzyme adopts an 'open conformation' in the absence of substrates or inhibitors with the two active site cysteines existing as a thiol-thiolate pair. Substrate binding to the C-terminal domain triggers the closure of the N-terminal domain coupled with tight encapsulation of the ligand, stabilization of the conformation of an active site loop containing Cys73 and expulsion of water molecules with concomitant desolvation of the thiolate base. This structural rearrangement is critical for catalysis.
 ...
PMID:Dynamics of catalysis revealed from the crystal structures of mutants of diaminopimelate epimerase. 1788 30

It has been postulated that infectious agents may precipitate autoimmune disease when T cell responses raised against the pathogen cross-react with self-peptides, a phenomenon known as molecular mimicry. However, there are very little data available characterizing the similarity between the repertoire of the cross-reactive self-specific T cell population compared with the pathogen-specific T cell repertoire. In this study, we use immunoscope analysis to identify the T cell populations induced upon priming SJL/J mice with a pathogen-derived mimic of the immunodominant encephalitogenic myelin peptide PLP(139-151), which is contained within the protease IV protein of Haemophilus influenzae (HAE(574-586)). We describe an IFN-gamma-producing Vbeta19(+) T cell population in HAE(574-586)-primed mice that appears to be the "public clonotype" as it expanded in response to peptide in all mice tested. Critically this Vbeta19(+) T cell population is not expanded in mice primed with the self-peptide PLP(139-151), indicating that mimics can induce the expansion of new self-reactive populations not initially present in the periphery of a host. This is the first description of the use of immunoscope analysis to characterize the cross-reactive anti-self T cell response induced by a molecular mimic.
 ...
PMID:Molecular mimics can induce novel self peptide-reactive CD4+ T cell clonotypes in autoimmune disease. 1798 50

O-Acetylserine sulfhydrylase (isoform A, OASS-A) is a PLP-dependent enzyme involved in the last step of cysteine biosynthesis in many pathogens. Many microorganisms use cysteine as the main building block for sulfur-containing antioxidants, and cysteine depletion in several pathogens resulted in a reduced antibiotic resistance, thus leading to the identification of OASS as novel suitable molecular targets to overcome antimicrobial resistances. The precise molecular mechanism of OASS-A inhibition by small peptides or by small molecule inhibitors is still unclear. To shed more lights on the structural basis underlying the inhibition mechanism for OASS, we engaged ourselves in studying the dynamic properties of this enzyme. In this paper, we describe a computational study involving unbiased MD simulations of OASS-A from Haemophilus influenzae (HiOASS) in its inhibitor free, PLP-bound form, and in complex with a pentapeptide inhibitor and with UPAR40, a small molecule which we have recently reported as a potent OASS-A inhibitors. We proposed that UPAR40 inhibits HiOASS-A through the stabilization of a closed conformation. Moreover, preliminary docking studies and sequence analysis allow us to speculate about the non-specificity of UPAR40 toward a particular OASS enzyme species or isoforms.
...
PMID:Computational Insights into the Mechanism of Inhibition of OASS-A by a Small Molecule Inhibitor. 2748 65