[This corrects the article on p. 100 in vol. 41.].

Energy conservation in chemotrophic anaerobic bacteria.

https://stacks.cdc.gov/view/cdc/34113/cdc_34113_DS1.pdf

Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis.

Molybdenum is the only second-row transition metal required by most living organisms, and is nearly universally distributed in biology. Enzymes containing molybdenum in their active sites have long been recognized,1 and at present over 50 molybdenum-containing enzymes have been purified and biochemically characterized; a great many more gene products have been annotated as putative molybdenum-containing proteins on the basis of genomic and bioinformatic analysis.2 In certain cases, our understanding of the relationship between enzyme structure and function is such that we can speak with confidence as to the detailed nature of the reaction mechanism and, with the availability of high-resolution X-ray crystal structures, the specific means by which transition states are stabilized and reaction rate is accelerated within the friendly confines of the active site. At the same time, our understanding of the biosynthesis of the organic cofactor that accompanies molybdenum (variously called molybdopterin or pyranopterin), the manner in which molybdenum is incorporated into it, and then further modified as necessary prior to insertion into apoprotein has also (in at least some cases) become increasingly well understood.

It is now well-established that all molybdenum-containing enzymes other than nitrogenase (in which molybdenum is incorporated into a [MoFe7S9] cluster of the active site) fall into three large and mutually exclusive families, as exemplified by the enzymes xanthine oxidase, sulfite oxidase, and DMSO reductase; these enzymes represent the focus of the present account.3 The structures of the three canonical molybdenum centers in their oxidized Mo(VI) states are shown in Figure 1, along with that for the pyranopterin cofactor. The active sites of members of the xanthine oxidase family have an LMoVIOS-(OH) structure with a square-pyramidal coordination geometry. The apical ligand is a Mo=O ligand, and the equatorial plane has two sulfurs from the enedithiolate side chain of the pyranopterin cofactor, a catalytically labile Mo–OH group, and most frequently a Mo=S. Nonfunctional forms of these enzymes exist in which the equatorial Mo=S is replaced with a second Mo=O; in at least one member of the family the Mo=S is replaced by a Mo=Se, and in others it is replaced by a more complex –S–Cu–S–Cys to give a binuclear center. Members of the sulfite oxidase family have a related LMoVIO2(S–Cys) active site, again square-pyramidal with an apical Mo=O and a bidentate enedithiolate Ligand (L) in the equatorial plane but with a second equatorial Mo=O (rather than Mo–OH) and a cysteine ligand contributed by the protein (rather than a Mo=S) completing the molybdenum coordination sphere. The final family is the most diverse structurally, although all members possess two (rather than just one) equiv of the pyranopterin cofactor and have an L2MoVIY(X) trigonal prismatic coordination geometry. DMSO reductase itself has a catalytically labile Mo=O as Y and a serinate ligand as X completing the metal coordination sphere of oxidized enzyme. Other family members have cysteine (the bacterial Nap periplasmic nitrate reductases), selenocysteine (formate dehydrogenase H), –OH (arsenite oxidase), or aspartate (the NarGHI dissimilatory nitrate reductases) in place of the serine. Some enzymes have S or even Se in place of the Mo=O group. Members of the DMSO reductase family exhibit a general structural homology to members of the aldehyde:ferredoxin oxidoreductase family of tungsten-containing enzymes;4 indeed, the first pyranopterin-containing enzyme to be crystallographically characterized was the tungsten-containing aldehyde:ferredoxin oxidoreductase from Pyrococcus furiosus,5 a fact accounting for why many workers in the field prefer “pyranopterin” (or, perhaps waggishly, “tungstopterin”) to “molybdopterin”. The term pyranopterin will generally be used in the present account.




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Figure 1


Active site structures for the three families of mononuclear molybdenum enzymes. The structures shown are, from left to right, for xanthine oxidase, sulfite oxidase, and DMSO reductase. The structure of the pyranopterin cofactor common to all of these enzymes (as well as the tungsten-containing enzymes) is given at the bottom.

/pdf/the-mononuclear-molybdenum-enzymes-huemv59go8.pdf

The Mononuclear Molybdenum Enzymes

Rheumatoid arthritis (RA) is a widely prevalent (1-3%) chronic systemic disease thought to have an autoimmune component; both humoral and cellular mechanisms have been implicated. Primary osteoarthritis (OA) is considered to be distinct from rheumatoid arthritis, and here damage is thought to be secondary to cartilage degeneration. In rheumatoid arthritis, immune complexes are present that consist exclusively of immunoglobulin, implying that this is both the 'antibody' (rheumatoid factor [RF]) and the 'antigen' (most commonly IgG). Autoantigenic reactivity has been localized to the constant-region (C gamma 2) domains of IgG. There is no evidence for a polypeptide determinant but carbohydrate changes have been reported. We have therefore conducted a study, simultaneously in Oxford and Tokyo, to compare in detail the N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results, which required an evaluation of the primary sequences of approximately 1,400 oligosaccharides from 46 IgG samples, indicate that: (1) IgG isolated from normal individuals, patients with RA and patients with OA contains different distributions of asparagine-linked bi-antennary complex-type oligosaccharide structures, (2) in neither disease is the IgG associated with novel oligosaccharide structures, but the observed differences are due to changes in the relative extent of galactosylation compared with normal individuals. This change results in a 'shift' in the population of IgG molecules towards those carrying complex oligosaccharides, one or both of whose arms terminate in N-acetylglucosamine. These two arthritides may therefore be glycosylation diseases, reflecting changes in the intracellular processing, or post-secretory degradation of N-linked oligosaccharides.

/pdf/association-of-rheumatoid-arthritis-and-primary-af3mchbweb.pdf

Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG.

We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL.

/pdf/definition-of-organ-involvement-and-treatment-response-in-35dh41rrhf.pdf

Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

Tumor immunity in patients with primary intracranial tumors was assessed in relation to the general status of host immunocompetence. Lymphocyte sensitization to tumor-specific membrane antigens was demonstrated by the proliferative response of lymphocytes in the presence of autochthonous tumor cells. Paradoxically, one-half of the patients could not be sensitized to a primary antigen, dinitrochlorobenzene; existing delayed hypersensitivity was also depressed, as measured by skin tests and lymphocyte transformation in response to common antigens. A heat-stable factor in patients' sera blocked cell-mediated tumor immunity. In addition, these "enhancing" sera consistently suppressed the blastogenic response of autologous and homologous lymphocytes to phytohemagglutinin and to membrane antigens on allogeneic cells in the one-way mixed lymphocyte culture. When patients' leukocytes were washed and autologous plasma replaced with normal plasma, reactivity in the mixed lymphocyte culture increased to normal values. In vitro immunosuppressive activity in patients' plasma or sera correlated with depressed delayed hypersensitivity. After removal of the tumor, suppressor activity disappeared. IgG fractions of patient sera contained strong immunosuppressive activity. These data suggest that the suppressor factor may be an isoantibody elicited by the tumor that also binds to receptors on the lymphocyte membrane. In addition to specifically blocking cell-mediated tumor immunity, enhancing sera may broadly depress host immunocompetence.

https://rupress.org/jem/article-pdf/136/6/1631/1085082/1631.pdf

Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor.

Purification and properties of nitrate reductase from Escherichia coli K12.

Lymphocyte Subsets in Normal Bone Marrow

Antibody against a cross-reactive idiotype (CRI) on human IgM-rheumatoid factor (RF) antibodies was induced by immunization of rabbits with a synthetic peptide ( PSL2 ) corresponding to the second complementarity-determining region (CDR), and adjacent amino acid residues of the kappa light chain of the IgM-RF Sie . The anti-peptide antibody bound efficiently to IgM-RF proteins known to share a cross-reactive idiotype, and to their isolated kappa chains. The anti-CRI was absorbed by, and eluted from, a peptide-Sepharose affinity column. The antibody activity was inhibited by the free peptide in solution. The anti-peptide antibody thus identifies a public idiotype on human IgM-RF, that is largely dependent on the primary sequence of the second CDR of the light chain. Such peptide-induced antiidiotypes of predefined specificity may facilitate studies of the molecular basis of idiotypic cross-reactions, the inheritance and somatic diversification of antibody molecules, and the regulation of the idiotype network.

https://rupress.org/jem/article-pdf/159/5/1502/1094337/1502.pdf

David E. Normansell

Papers

Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor.

Purification and properties of nitrate reductase from Escherichia coli K12.

Lymphocyte Subsets in Normal Bone Marrow

Delineation of a cross-reactive idiotype on human autoantibodies with antibody against a synthetic peptide.

Anti-γ-globulins in rheumatoid arthritis sera—III. The reactivity of anti-γ-globulin rheumatoid factors with heterologous γG-globulin