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Multiple-scattering (MS) analysis of EXAFS data on met-indoleamine 2,3-dioxygenase-2 (IDO2) and analysis of XANES have provided the first direct structural information about the axial donor ligands of the iron center for this recently discovered protein. At 10K, it exists in a low-spin bis(His) form with Fe-Np(av)=1.97Å, the Fe-NIm bond lengths of 2.11Å and 2.05Å, which is in equilibrium with a high-spin form at room temperature. The bond distances in the low-spin form are consistent with other low-spin hemeproteins, as is the XANES spectrum, which is closer to that of the low-spin met-Lb than that of the high-spin met-Mb. The potential physiological role of this spin equilibrium is discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2α phosphorylation, which precedes activation of autophagy and apoptosis., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The hemoprotein indoleamine 2,3-dioxygenase-1 (IDO1) is the first and rate-limiting enzyme in mammalian tryptophan metabolism. Interest in IDO1 continues to grow, due to the ever expanding influence IDO1 plays in the immune response. This study examined the contribution of all individual cysteine residues towards the overall catalytic properties and stability of recombinant human IDO1 via mutagenesis studies using a range of biochemical and spectroscopic techniques, including in vitro kinetic assessment, secondary structure identification via circular dichroism spectroscopy and thermal stability assessment. Upon mutation of cysteine residues we observed changes in secondary structure (principally, shifting from α-helix/β-sheet features to random coil structures) that produced out of plane heme torsion and puckering, changes to thermal stability (including gains in stability for one mutant protein) and differences in enzymatic activity (such as, increased ability to convert non-natural substrates, e.g.d-tryptophan) from wild type IDO1 enzyme., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The translocator protein (TSPO) is an 18 kDa transmembrane protein primarily found in the outer mitochondrial membrane where it forms a key part of the mitochondrial permeability transition pore (MPTP). Omnipresent in almost all tissues, TSPO up-regulation has been connected to neuronal damage and inflammation, making the protein an important bio-imaging marker for disease progression. More recently, TSPO has attracted attention as a possible molecular target for tumour imaging and chemotherapy. In this review we summarize TSPO's molecular characteristics and highlight research progress in recent years in the field of TSPO-targeted cancer diagnostics and treatments., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

The kynurenine pathway of tryptophan metabolism converts the amino acid tryptophan into a number of biologically active metabolites. The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formylkynurenine and until recently this reaction was thought to be performed by either of two enzymes, tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase. A third enzyme, indoleamine 2,3-dioxygenase-2, indoleamine 2,3-dioxygenase-like protein or proto-indoleamine 2,3-dioxygenase (IDO2, IDO-2, INDOL1 or proto-IDO), with this activity recently has been described. The gene encoding IDO2 is adjacent and structurally similar to the indoleamine 2,3-dioxygenase gene and both mouse genes use multiple promoters to express transcripts with alternate 5' exons. The IDO2 protein is expressed in the murine kidney, liver, male and female reproductive system. The two IDO enzymes can utilise a similar range of substrates, however they differ in their selectivity for some inhibitors. The selective inhibition of IDO2 by 1-methyl-D-tryptophan suggests that IDO2 activity may have a role in the inhibition of immune responses to tumours.