Zinc Cofactor Research Articles

Exploring the Pharmacological Potential of Carrageenan Disaccharides as Antitumor Agents: An In Silico Approach.

Carrageenans have demonstrated enhanced antitumor activity upon depolymerization into disaccharides. However, the pharmacological viability of these disaccharides and their mechanisms of antitumor action remains to be fully elucidated. This study aimed to employ computational tools to investigate the pharmacological properties and molecular targets pertinent to cancer of the disaccharides derived from the primary carrageenans. Analyses of pharmacological properties predicted by the pkCSM and SwissADME servers indicated that the disaccharides possess a favorable pharmacokinetic profile, although they encounter permeability challenges primarily due to their high polarity and low lipophilicity. Target prediction using SwissTarget and PPB2 identified five carbonic anhydrases, which are also targets of oncology drugs, as common targets for the disaccharides. Molecular docking performed with AutoDock Vina revealed that the binding energies of the disaccharides with carbonic anhydrases were comparable to or greater than those of existing drugs that target these lyases. Notably, six of the complexes formed exhibited interactions between the disaccharides and the zinc cofactor, which represents a primary mechanism of inhibition for these targets. Furthermore, molecular dynamics simulations conducted using GROMACS demonstrated a stable interaction between the disaccharides and carbonic anhydrases. These findings offer new insights into the pharmacological properties and mechanisms of action of carrageenan-derived disaccharides, highlighting their potential for further exploration in clinical trials and experimental studies.

Identification of novel nutrient sensitive human yolk sac functions required for embryogenesis

The human yolk sac (hYS) is essential for embryo nutrient biosynthesis/transport and development. However, there lacks a comprehensive study of hYS nutrient-gene interactions. Here we performed a secondary analysis of hYS transcript profiles (n = 9 samples) to identify nutrient-sensitive hYS genes and regulatory networks, including those that associate with adverse perinatal phenotypes with embryonic origins. Overall, 14.8% highly expressed hYS genes are nutrient-sensitive; the most common nutrient cofactors for hYS genes are metals and B vitamins. Functional analysis of highly expressed hYS genes reveals that nutrient-sensitive hYS genes are more likely to be involved in metabolic functions than hYS genes that are not nutrient-sensitive. Through nutrient-sensitive gene network analysis, we find that four nutrient-sensitive transcription regulators in the hYS (with zinc and/or magnesium cofactors) are predicted to collectively regulate 30.9% of highly expressed hYS genes. Lastly, we identify 117 nutrient-sensitive hYS genes that associate with an adverse perinatal outcome with embryonic origins. Among these, the greatest number of nutrient-sensitive hYS genes are linked to congenital heart defects (n = 54 genes), followed by microcephaly (n = 37). Collectively, our study characterises nutrient-sensitive hYS functions and improves understanding of the ways in which nutrient-gene interactions in the hYS may influence both typical and pathological development.

A study of bacteria producing carbonic anhydrase enzyme for CaCO3 precipitation and soil biocementation

We study the carbonic anhydrase (CA) pathway using autochthonous CA-producing bacteria as a means of inducing calcite precipitation, which acts as a biocement to improve the engineering soil properties. Forty different microbial strains producing CA were isolated from the foundation soil of a railway embankment in Prickwillow, UK. Three of the best CA-producing strains were selected and identified by DNA sequencing as Bacillus licheniformis, Bacillus toyonensis and Bacillus pumilus with CA activity values respectively of 1.79 U/ml, 1.42 U/ml and 1.55 U/ml. To optimise the treatments, we investigated the effect of pH, temperature, zinc co-factor and cementation solution molarity on the growth and CA activity and bioprecipitates, with CO2 added in the form of bicarbonate. Scanning electron microscope (SEM) analysis of the bioprecipitates showed that these had characteristic morphologies of calcite and vaterite crystals. The formation of calcite was further corroborated by FT-IR and Raman analysis of bioprecipitates. The precultured bacteria were injected into the fine-grained soil together with cementation solution. Unconfined compressive strength in treated soil increased up to 1 MPa, and its calcium carbonate content increased by 2.78%. This, as well as the stability of the treated soil upon water immersion, proved the biocementation of the fine-grained soil. These findings suggest the potential of employing the CA biocementation route for soil stabilisation pending further development of the technique.

Suboptimal zinc supply affects the S-nitrosoglutathione reductase enzyme and nitric oxide signaling in Arabidopsis

Suboptimal zinc supply affects the S-nitrosoglutathione reductase enzyme and nitric oxide signaling in Arabidopsis

Gold drugs as colistin adjuvants in the fight against MCR-1 producing bacteria.

The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance.

Genetic architecture and evolution of color variation in American black bears

Color variation is a frequent evolutionary substrate for camouflage in small mammals, but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus (U.americanus), exhibits a range of colors including the cinnamon morph, which has a similar color to the brown bear, U.arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U.arctos and cinnamon U.americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U.americanus individuals and identified a single major locus (p<10-13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that likely affects binding of the zinc cofactor, impairs protein localization, and results in decreased pigment production. Population genetic analyses and demographic modeling indicated that the R153C variant arose 9.36 kya in a southwestern population where it likely provided a selective advantage, spreading both northwards and eastwards by gene flow. A different TYRP1 allele, R114C, contributes to the characteristic brown color of U.arctos but is not fixed across the range.

Anti-seizure effect of zinc on PTZ-induced epilepsy in rat model.

Epilepsy is a widespread and mainly severe neurological condition portrayed by recurring spontaneous seizures caused by the brain's abnormal electrical activity. According to new research, inflammation may be both a result and the cause of epileptic seizures. The highest zinc levels in the brain have been found in the hippocampus which is one of the most studied regions of the brain regarding epilepsy. Zinc may have an anti-inflammatory potential as zinc co-factors affect numerous biochemical and physiological reactions. In this study, we evaluated the effects of intraperitoneal zinc administration on seizure activity in murine PTZ model. Rats received either intraperitoneal (IP) zinc sulfate at two different dosages (50-100 mg/kg) or a placebo followed by pentylenetetrazole (IP), a strong seizure-inducing drug. The spike percentages were considerably lower in the PTZ (35 mg/kg) and 50 or 100 mg/kg zinc-treated groups (A3 and A4) than in the PTZ (35 mg/kg) and saline-treated group (A2; p may be used as an adjuvant therapy in combination with other antiepileptic drugs in the future (Tab. 3, Fig. 1, Ref. 27) Keywords: anti-seizure effect of zinc, epilepsy, abnormal electrical activity, antiepileptic drugs, rat model.

Timing the evolution of antioxidant enzymes in cyanobacteria

The ancestors of cyanobacteria generated Earth’s first biogenic molecular oxygen, but how they dealt with oxidative stress remains unconstrained. Here we investigate when superoxide dismutase enzymes (SODs) capable of removing superoxide free radicals evolved and estimate when Cyanobacteria originated. Our Bayesian molecular clocks, calibrated with microfossils, predict that stem Cyanobacteria arose 3300–3600 million years ago. Shortly afterwards, we find phylogenetic evidence that ancestral cyanobacteria used SODs with copper and zinc cofactors (CuZnSOD) during the Archaean. By the Paleoproterozoic, they became genetically capable of using iron, nickel, and manganese as cofactors (FeSOD, NiSOD, and MnSOD respectively). The evolution of NiSOD is particularly intriguing because it corresponds with cyanobacteria’s invasion of the open ocean. Our analyses of metalloenzymes dealing with reactive oxygen species (ROS) now demonstrate that marine geochemical records alone may not predict patterns of metal usage by phototrophs from freshwater and terrestrial habitats.

IN SILICO IDENTIFICATION OF APOBEC3B SMALL MOLECULE INHIBITORS FROM DTP-NCI LIBRARIES

Objective: APOBEC3B (A3B) enzyme causes C-to-T or C-to-G somatic alteration in the cancer genome, leading to the evolution of a broad spectrum of human cancers. The present study aims to identify A3B small molecule inhibitors using a top-down approach via pharmacoinformatic virtual screening.&#x0D; Methods: Virtual screening of 2951 drug-alike molecules with diversified structures from the National Cancer Institute Development Therapeutics Program (DTP-NCI) compounds library was performed using GOLD and AutoDock Vina docking programs against the 3D structure of A3B (PDB ID: 5TD5).&#x0D; Results: Amongst the docked compounds, Nordracorubin, NSC641233 and Raloxifene hydrochloride showed the most potent binding affinities towards A3B on both Autodock/Vina and GOLD. Several significant similarities were observed between A3B and the three hits, including hydrogen bonds and pi-pi stacking. The three compounds also exhibited interaction with the centralized zinc cofactor and amino acid residues that directly contribute the deaminase activity of A3B enzyme.&#x0D; Conclusion: We hypothesize that the findings from this study could significantly shorten the quest for novel molecules against the A3B after confirmation with subsequent in vitro and in vivo studies in the near future.

Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

Manganese import protects Salmonella enterica serovar Typhimurium against nitrosative stress.

Nitric oxide (NO˙) is a radical molecule produced by mammalian phagocytic cells as part of the innate immune response to bacterial pathogens. It exerts its antimicrobial activity in part by impairing the function of metalloproteins, particularly those containing iron and zinc cofactors. The pathogenic Gram-negative bacterium Salmonella enterica serovar typhimurium undergoes dynamic changes in its cellular content of the four most common metal cofactors following exposure to NO˙ stress. Zinc, iron and magnesium all decrease in response to NO˙ while cellular manganese increases significantly. Manganese acquisition is driven primarily by increased expression of the mntH and sitABCD transporters following derepression of MntR and Fur. ZupT also contributes to manganese acquisition in response to nitrosative stress. S. Typhimurium mutants lacking manganese importers are more sensitive to NO˙, indicating that manganese is important for resistance to nitrosative stress.

Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase.

Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), we tested the inhibitory activity of peptidomimetic compounds designed as inhibitors of matrix metalloproteinases on the activities of the SVMP Batx-I, from Bothrops atrox venom. The evaluated compounds show great potential for the inhibition of Batx-I proteolytic, hemorrhagic and edema-forming activities, especially the compound CP471474, a peptidomimetic including a hydroxamate zinc binding group. Molecular dynamics simulations suggest that binding of this compound to the enzyme is mediated by the electrostatic interaction between the hydroxamate group and the zinc cofactor, as well as contacts, mainly hydrophobic, between the side chain of the compound and amino acids located in the substrate binding subsites S1 and S1. These results show that CP471474 constitutes a promising compound for the development of co-adjuvants to neutralize local tissue damage induced by snake venom metalloproteinases.

Prediction of zinc-binding sites using multiple sequence profiles and machine learning methods.

The zinc (Zn2+) cofactor has been proven to be involved in numerous biological mechanisms and the zinc-binding site is recognized as one of the most important post-translation modifications in proteins. Therefore, accurate knowledge of zinc ions in protein structures can provide potential clues for elucidation of protein folding and functions. However, determining zinc-binding residues by experimental means is usually lab-intensive and associated with high cost in most cases. In this context, the development of computational tools for identifying zinc-binding sites is highly desired, especially in the current post-genomic era. In this work, we developed a novel zinc-binding site prediction method by combining several intensively-trained machine learning models. To establish an accurate and generative method, we downloaded all zinc-binding proteins from the Protein Data Bank and prepared a non-redundant dataset. Meanwhile, a well-prepared dataset by other groups was also used. Then, effective and complementary features were extracted from sequences and three-dimensional structures of these proteins. Moreover, several well-designed machine learning models were intensively trained to construct accurate models. To assess the performance, the obtained predictors were stringently benchmarked using the diverse zinc-binding sites. Furthermore, several state-of-the-art in silico methods developed specifically for zinc-binding sites were also evaluated and compared. The results confirmed that our method is very competitive in real world applications and could become a complementary tool to wet lab experiments. To facilitate research in the community, a web server and stand-alone program implementing our method were constructed and are publicly available at . The downloadable program of our method can be easily used for the high-throughput screening of potential zinc-binding sites across proteomes.

Interactions between Triterpenes and a P-I Type Snake Venom Metalloproteinase: Molecular Simulations and Experiments.

Small molecule inhibitors of snake venom metalloproteinases (SVMPs) could provide a means to rapidly halt the progression of local tissue damage following viperid snake envenomations. In this study, we examine the ability of candidate compounds based on a pentacyclic triterpene skeleton to inhibit SVMPs. We leverage molecular dynamics simulations to estimate the free energies of the candidate compounds for binding to BaP1, a P-I type SVMP, and compare these results with experimental assays of proteolytic activity inhibition in a homologous enzyme (Batx-I). Both simulation and experiment suggest that betulinic acid is the most active candidate, with the simulations predicting a standard binding free energy of kcal/mol. The simulations also reveal the atomic interactions that underlie binding between the triterpenic acids and BaP1, most notably the electrostatic interaction between carboxylate groups of the compounds and the zinc cofactor of BaP1. Together, our simulations and experiments suggest that occlusion of the S1 subsite is essential for inhibition of proteolytic activity. While all active compounds make hydrophobic contacts in the S1 site, -boswellic acid, with its distinct carboxylate position, does not occlude the S1 site in simulation and exhibits negligible activity in experiment.

Metal cofactor modulated folding and target recognition of HIV-1 NCp7.

The HIV-1 nucleocapsid 7 (NCp7) plays crucial roles in multiple stages of HIV-1 life cycle, and its biological functions rely on the binding of zinc ions. Understanding the molecular mechanism of how the zinc ions modulate the conformational dynamics and functions of the NCp7 is essential for the drug development and HIV-1 treatment. In this work, using a structure-based coarse-grained model, we studied the effects of zinc cofactors on the folding and target RNA(SL3) recognition of the NCp7 by molecular dynamics simulations. After reproducing some key properties of the zinc binding and folding of the NCp7 observed in previous experiments, our simulations revealed several interesting features in the metal ion modulated folding and target recognition. Firstly, we showed that the zinc binding makes the folding transition states of the two zinc fingers less structured, which is in line with the Hammond effect observed typically in mutation, temperature or denaturant induced perturbations to protein structure and stability. Secondly, We showed that there exists mutual interplay between the zinc ion binding and NCp7-target recognition. Binding of zinc ions enhances the affinity between the NCp7 and the target RNA, whereas the formation of the NCp7-RNA complex reshapes the intrinsic energy landscape of the NCp7 and increases the stability and zinc affinity of the two zinc fingers. Thirdly, by characterizing the effects of salt concentrations on the target RNA recognition, we showed that the NCp7 achieves optimal balance between the affinity and binding kinetics near the physiologically relevant salt concentrations. In addition, the effects of zinc binding on the inter-domain conformational flexibility and folding cooperativity of the NCp7 were also discussed.

RNA editing of plastid-encoded genes

RNA editing is post-transcriptional modification to RNA molecules. In plants, RNA editing primarily occurs to two energy-producing organelles: plastids and mitochondria. Organelle RNA editing is often viewed as a mechanism of correction to compensate for defects or mutations in haploid organelle genomes. A common type of organelle RNA editing is deamination from cytidine to uridine. Cytidine-to-uridine plastid RNA editing is carried out by the RNA editing complex which consists of at least four types of proteins: pentatricopeptide repeat proteins, RNA editing interacting proteins/multiple organellar RNA editing factors, organelle RNA recognition motif proteins, and organelle zinc-finger proteins. The four types of RNA editing factors work together to carry out RNA editing site recognition, zinc cofactor binding, and cytidine-to-uridine deamination. In addition, three other types of proteins have been found to be important for plastid RNA editing. These additional proteins may play a regulatory or stabilizing role in the RNA editing complex.

Identification of an oxytocinase/vasopressinase-like leucyl-cystinyl aminopeptidase (LNPEP) in teleost fish and evidence for hypothalamic mRNA expression linked to behavioral social status

The vasotocin/vasopressin and isotocin/mesotocin/oxytocin family of nonapeptides regulate social behaviors and physiological functions associated with reproductive physiology and osmotic balance. While experimental and correlative studies provide evidence for these nonapeptides as modulators of behavior across all classes of vertebrates, mechanisms for nonapeptide inactivation in regulating these functions have been largely overlooked. Leucyl-cystinyl aminopeptidase (LNPEP) - also known as vasopressinase, oxytocinase, placental leucine aminopeptidase (P-LAP), and insulin-regulated aminopeptidase (IRAP) - is a membrane-bound zinc-dependent metalloexopeptidase enzyme that inactivates vasopressin, oxytocin, and select other cyclic polypeptides. In humans, LNPEP plays a key role in the clearance of oxytocin during pregnancy. However, the evolutionary diversity, expression distribution, and functional roles of LNPEP remain unresolved for other vertebrates. Here, we isolated and sequenced a full-length cDNA encoding a LNPEP-like polypeptide of 1033 amino acids from the ovarian tissue of Amargosa pupfish, Cyprinodon nevadensis. This deduced polypeptide exhibited high amino acid identity to human LNPEP both in the protein's active domain that includes the peptide binding site and zinc cofactor binding motif (53.1% identity), and in an intracellular region that distinguishes LNPEP from other aminopeptidases (70.3% identity). Transcripts encoding this LNPEP enzyme (lnpep) were detected at highest relative abundance in the gonads, hypothalamus, forebrain, optic tectum, gill and skeletal muscle of adult pupfish. Further evaluation of lnpep transcript abundance in the brain of sexually-mature pupfish revealed that lnpep mRNAs were elevated in the hypothalamus of socially subordinate females and males, and at lower abundance in the telencephalon of socially dominant males compared to dominant females. These findings provide evidence of an association between behavioral social status and hypothalamic lnpep transcript abundance and suggest that variation in the rate of VT/IT peptide inactivation by LNPEP may be a contributing component in the mechanism whereby nonapeptides regulate social behavior.

Zinc ion-induced conformational changes in new Delphi metallo-β-lactamase 1 probed by molecular dynamics simulations and umbrella sampling.

The hydrolysis of a β-lactam core ring caused by new Delphi metallo-β-lactamase 1 (NDM-1) with the help of two zinc cofactors induces significant resistance toward β-lactam antibiotics. Molecular dynamics (MD) simulations and the umbrella sampling method are integrated to study the conformational change mechanism of NDM-1 mediated by zinc ion binding. The statistical analyses of interaction contacts of the antibiotic ampicillin (AMP) with residues based on MD trajectories suggest that two Zn ions are essential for maintaining the binding of AMP with NDM-1. Umbrella sampling simulations further reveal that double-Zn coordination exerts strong restriction on the motions of loop L10 relative to loops L3 and L4. Principal component (PC) analysis also demonstrates that zinc ion binding totally inhibits the motion extent of NDM-1 and changes internal motion modes in NDM-1. We expect that the current study can provide significant dynamical information involving conformational changes of NDM-1 for the development of efficient inhibitors to decrease drug resistance of NDM-1 toward antibiotics.

Fundamental Role of Methylenetetrahydrofolate Reductase 677 C → T Genotype and Flavin Compounds in Biochemical Phenotypes for Schizophrenia and Schizoaffective Psychosis.

The Mental Health Biomarker Project (2010–2016) explored variables for psychosis in schizophrenia and schizoaffective disorder. Blood samples from 67, highly characterized symptomatic cases and 67 gender and age matched control participants were analyzed for methyl tetrahydrofolate reductase (MTHFR) 677C → T gene variants and for vitamin B6, B12 and D, folate, unbound copper, zinc cofactors for enzymes in the methylation cycle, and related catecholamine pathways. Urine samples were analyzed for indole-catecholamines, their metabolites, and oxidative-stress marker, hydroxylpyrolline-2-one (HPL). Rating scales were Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale, Global Assessment of Function scale, Clinical Global Impression (CGI) score, and Social and Occupational Functioning Assessment Scale (SOFAS). Analysis used Spearman’s correlates, receiver operating characteristics and structural equation modeling (SEM). The correlative pattern of variables in the overall participant sample strongly implicated monoamine oxidase (MAO) enzyme inactivity so the significant role of MAO’s cofactor flavin adenine nucleotide and its precursor flavin adenine mononucleotide (FMN) within the biochemical pathways was investigated and confirmed as 71% on SEM of the total sample. Splitting the data sets for MTHFR 677C → T polymorphism variants coding for the MTHFR enzyme, discovered that biochemistry variables relating to the wild-type enzyme differed markedly in pattern from those coded by the homozygous variant and that the hereozygous-variant pattern resembled the wild-type-coded pattern. The MTHFR 677C → T-wild and -heterozygous gene variants have a pattern of depleted vitamin cofactors characteristic of flavin insufficiency with under-methylation and severe oxidative stress. The second homozygous MTHFR 677TT pattern related to elevated copper:zinc ratio and a vitamin pattern related to flavin sufficiency and risk of over-methylation. The two gene variants and their different biochemical phenotypes govern findings in relationship to case-identification, illness severity, duration of illness, and functional disability in schizophrenia and schizoaffective psychosis, and establish a basis for trials of gene-guided precision treatment for the management of psychosis.

The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases

In eukaryotes the bimetallic Cu/Zn superoxide dismutase (SOD) enzymes play important roles in the biology of reactive oxygen species by disproportionating superoxide anion. Recently, we reported that the fungal pathogen Candida albicans expresses a novel copper-only SOD, known as SOD5, that lacks the zinc cofactor and electrostatic loop (ESL) domain of Cu/Zn-SODs for substrate guidance. Despite these abnormalities, C. albicans SOD5 can disproportionate superoxide at rates limited only by diffusion. Here we demonstrate that this curious copper-only SOD occurs throughout the fungal kingdom as well as in phylogenetically distant oomycetes or "pseudofungi" species. It is the only form of extracellular SOD in fungi and oomycetes, in stark contrast to the extracellular Cu/Zn-SODs of plants and animals. Through structural biology and biochemical approaches we demonstrate that these copper-only SODs have evolved with a specialized active site consisting of two highly conserved residues equivalent to SOD5 Glu-110 and Asp-113. The equivalent positions are zinc binding ligands in Cu/Zn-SODs and have evolved in copper-only SODs to control catalysis and copper binding in lieu of zinc and the ESL. Similar to the zinc ion in Cu/Zn-SODs, SOD5 Glu-110 helps orient a key copper-coordinating histidine and extends the pH range of enzyme catalysis. SOD5 Asp-113 connects to the active site in a manner similar to that of the ESL in Cu/Zn-SODs and assists in copper cofactor binding. Copper-only SODs are virulence factors for certain fungal pathogens; thus this unique active site may be a target for future anti-fungal strategies.