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Background Peptides radiolabeled with fluorine-18 are frequently synthesized using prosthetic groups. Among them, activated esters of 6-[ 18 F]fluoronicotinic acid ([ 18 F]FNA) have been prepared and successfully employed for 18 F-labeling of diverse biomolecules, including peptides. The utility of [ 18 F]FNA as a prosthetic compound has been demonstrated in both preclinical and clinical settings, including radiopharmaceuticals targeting prostate-specific membrane antigen and poly(ADP ribose) polymerase inhibitors. This study aims to evaluate a [ 18 F]FNA-conjugated nonapeptide, [ 18 F]FNA- N -CooP, for positron emission tomography imaging of intracranial BT12 glioblastoma xenografts in a mouse model. Additionally, this study highlights the importance of including control experiments with prosthetic compound alone when it constitutes a major radiometabolite. Results [ 18 F]FNA- N -CooP successfully delineated intracranial glioblastoma xenografts yielding a standardized uptake value of 0.21 ± 0.03 ( n  = 4) and a tumor-to-brain ratio of 1.84 ± 0.29. Ex vivo autoradiography of tumor tissue showed a partial co-localization between radioactivity uptake and the target fatty acid binding protein 3 expression. However, in vivo instability of [ 18 F]FNA- N -CooP was observed, with [ 18 F]FNA identified as a major radiometabolite. Notably, control studies using [ 18 F]FNA alone also visualized tumors, producing a standardized uptake value of 0.90 ± 0.10 ( n  = 4) and a tumor-to-brain ratio of 1.51 ± 0.08. Conclusions Both [ 18 F]FNA- N -CooP and [ 18 F]FNA enabled PET visualization of human glioblastoma in the mouse model. However, the prominent presence of [ 18 F]FNA as radiometabolite complicates the interpretation of [ 18 F]FNA- N -CooP PET data, suggesting that the observed radioactivity uptake may primarily originate from [ 18 F]FNA and other radiometabolites. Enhancing peptide stability is essential for improving imaging specificity. This study underscores the critical need to assess the imaging contributions of prosthetic groups when they function as significant radiometabolites.

The concept of a last universal common ancestor of all cells (LUCA, or the progenote) is central to the study of early evolution and life's origin, yet information about how and where LUCA lived is lacking. We investigated all clusters and phylogenetic trees for 6.1 million protein coding genes from sequenced prokaryotic genomes in order to reconstruct the microbial ecology of LUCA. Among 286,514 protein clusters, we identified 355 protein families (∼0.1%) that trace to LUCA by phylogenetic criteria. Because these proteins are not universally distributed, they can shed light on LUCA's physiology. Their functions, properties and prosthetic groups depict LUCA as anaerobic, CO 2 -fixing, H 2 -dependent with a Wood–Ljungdahl pathway, N 2 -fixing and thermophilic. LUCA's biochemistry was replete with FeS clusters and radical reaction mechanisms. Its cofactors reveal dependence upon transition metals, flavins, S -adenosyl methionine, coenzyme A, ferredoxin, molybdopterin, corrins and selenium. Its genetic code required nucleoside modifications and S -adenosyl methionine-dependent methylations. The 355 phylogenies identify clostridia and methanogens, whose modern lifestyles resemble that of LUCA, as basal among their respective domains. LUCA inhabited a geochemically active environment rich in H 2 , CO 2 and iron. The data support the theory of an autotrophic origin of life involving the Wood–Ljungdahl pathway in a hydrothermal setting. A phylogenetic approach was used to illuminate the physiology of the last universal common ancestor, supporting the theory that LUCA was an H 2 -dependent autotroph in a hydrothermal setting rich in hydrogen, carbon dioxide and iron.

Most life forms on Earth are supported by solar energy harnessed by oxygenic photosynthesis. In eukaryotes, photosynthesis is achieved by large membrane-embedded super-complexes, containing reaction centers and connected antennae. Here, we report the structure of the higher plant PSI-LHCI super-complex determined at 2.8 Å resolution. The structure includes 16 subunits and more than 200 prosthetic groups, which are mostly light harvesting pigments. The complete structures of the four LhcA subunits of LHCI include 52 chlorophyll a and 9 chlorophyll b molecules, as well as 10 carotenoids and 4 lipids. The structure of PSI-LHCI includes detailed protein pigments and pigment–pigment interactions, essential for the mechanism of excitation energy transfer and its modulation in one of nature's most efficient photochemical machines. Most plants, green algae and some bacteria use a process called photosynthesis to convert energy from sunlight into the chemical energy they need to survive and grow. With this energy, these organisms use carbon dioxide and water to create organic matter and release oxygen into the atmosphere. Therefore, photosynthesis plays a major role in providing the basis for life on earth. During photosynthesis, molecules of pigments known as chlorophyll and carotenoid capture the light energy. These pigments are contained within large groups (or ‘complexes’) of proteins that sit in membrane structures within cells. Two of the protein complexes—called photosystem I and LHCI—interact with each other to form a ‘supercomplex’ that transfers energy to a small protein called ferredoxin. To achieve this, the light energy captured by pigment molecules is transferred to other pigment molecules so that the energy is funneled towards the center of photosystem I. Mazor et al. used a technique called X-ray crystallography to create a very detailed three-dimensional model of photosystem I and LHCI from pea plants. The model shows how the twelve proteins of photosystem I are arranged in relation to the four proteins of the LHCI complex. The super-complex contains more than 200 other molecules, which are mostly chlorophylls and carotenoids. Of these, 61 chlorophyll molecules and ten carotenoid molecules are found in LHCI. The model also provides detailed information about how the pigments interact with each other and with the proteins in the supercomplex. Mazor et al.'s detailed model may help us to understand how these interactions allow photosystem I to harvest light energy with almost 100% efficiency, and aid efforts to develop new technologies that harness light.

One-pot enzymatic synthesis is flourishing in synthetic chemistry, heralding a sustainable and green era. Recent advancements enable the creation of complex enzymatic prosthetic groups and regeneration of enzymatic cofactors such as S-adenosylmethionine. The next frontier is to develop the effective and innovative cofactors for essential micronutrients, metabolic modulators, and biomedicines. One-pot enzymatic synthesis is flourishing in synthetic chemistry, heralding a sustainable and green era. Recent advancements enable the creation of complex enzymatic prosthetic groups and regeneration of enzymatic cofactors such as S-adenosylmethionine. The next frontier is to develop the effective and innovative cofactors for essential micronutrients, metabolic modulators, and biomedicines.

A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

Background The antimicrobial resistance (AMR) phenotypic properties, multiple drug resistance (MDR) gene profiles, and genes related to potential virulence and pathogenic properties of five Enterobacter bugandensis strains isolated from the International Space Station (ISS) were carried out and compared with genomes of three clinical strains. Whole genome sequences of ISS strains were characterized using the hybrid de novo assembly of Nanopore and Illumina reads. In addition to traditional microbial taxonomic approaches, multilocus sequence typing (MLST) analysis was performed to classify the phylogenetic lineage. Agar diffusion discs assay was performed to test antibiotics susceptibility. The draft genomes after assembly and scaffolding were annotated with the Rapid Annotations using Subsystems Technology and RNAmmer servers for downstream analysis. Results Molecular phylogeny and whole genome analysis of the ISS strains with all publicly available Enterobacter genomes revealed that ISS strains were E. bugandensis and similar to the type strain EB-247 T and two clinical isolates (153_ECLO and MBRL 1077). Comparative genomic analyses of all eight E. bungandensis strains showed, a total of 4733 genes were associated with carbohydrate metabolism (635 genes), amino acid and derivatives (496 genes), protein metabolism (291 genes), cofactors, vitamins, prosthetic groups, pigments (275 genes), membrane transport (247 genes), and RNA metabolism (239 genes). In addition, 112 genes identified in the ISS strains were involved in virulence, disease, and defense. Genes associated with resistance to antibiotics and toxic compounds, including the MDR tripartite system were also identified in the ISS strains. A multiple antibiotic resistance (MAR) locus or MAR operon encoding MarA, MarB, MarC, and MarR, which regulate more than 60 genes, including upregulation of drug efflux systems that have been reported in Escherichia coli K12, was also observed in the ISS strains. Conclusion Given the MDR results for these ISS Enterobacter genomes and increased chance of pathogenicity (PathogenFinder algorithm with > 79% probability), these species pose important health considerations for future missions. Thorough genomic characterization of the strains isolated from ISS can help to understand the pathogenic potential, and inform future missions, but analyzing them in in-vivo systems is required to discern the influence of microgravity on their pathogenicity.

With the advent of long-term human habitation in space and on the moon, understanding how the built environment microbiome of space habitats differs from Earth habitats, and how microbes survive, proliferate and spread in space conditions, is becoming more important. The microbial tracking mission series has been monitoring the microbiome of the International Space Station (ISS) for almost a decade. During this mission series, six unique strains of Gram-stain-positive bacteria, including two spore-forming and three non-spore-forming species, were isolated from the environmental surfaces of the ISS. The analysis of their 16S rRNA gene sequences revealed > 99% similarities with previously described bacterial species. To further explore their phylogenetic affiliation, whole genome sequencing was undertaken. For all strains, the gyrB gene exhibited < 93% similarity with closely related species, which proved effective in categorizing these ISS strains as novel species. Average nucleotide identity and digital DNA–DNA hybridization values, when compared to any known bacterial species, were < 94% and <50% respectively for all species described here. Traditional biochemical tests, fatty acid profiling, polar lipid, and cell wall composition analyses were performed to generate phenotypic characterization of these ISS strains. A study of the shotgun metagenomic reads from the ISS samples, from which the novel species were isolated, showed that only 0.1% of the total reads mapped to the novel species, supporting the idea that these novel species are rare in the ISS environments. In-depth annotation of the genomes unveiled a variety of genes linked to amino acid and derivative synthesis, carbohydrate metabolism, cofactors, vitamins, prosthetic groups, pigments, and protein metabolism. Further analysis of these ISS-isolated organisms revealed that, on average, they contain 46 genes associated with virulence, disease, and defense. The main predicted functions of these genes are: conferring resistance to antibiotics and toxic compounds, and enabling invasion and intracellular resistance. After conducting antiSMASH analysis, it was found that there are roughly 16 cluster types across the six strains, including β-lactone and type III polyketide synthase (T3PKS) clusters. Based on these multi-faceted taxonomic methods, it was concluded that these six ISS strains represent five novel species, which we propose to name as follows: Arthrobacter burdickii IIF3SC-B10 T (= NRRL B-65660 T = DSM 115933 T ), Leifsonia virtsii F6_8S_P_1A T (= NRRL B-65661 T = DSM 115931 T ), Leifsonia williamsii F6_8S_P_1B T (= NRRL B-65662 T = DSM 115932 T ), Paenibacillus vandeheii F6_3S_P_1C T (= NRRL B-65663 T = DSM 115940 T ), and Sporosarcina highlanderae F6_3S_P_2 T (= NRRL B-65664 T = DSM 115943 T ). Identifying and characterizing the genomes and phenotypes of novel microbes found in space habitats, like those explored in this study, is integral for expanding our genomic databases of space-relevant microbes. This approach offers the only reliable method to determine species composition, track microbial dispersion, and anticipate potential threats to human health from monitoring microbes on the surfaces and equipment within space habitats. By unraveling these microbial mysteries, we take a crucial step towards ensuring the safety and success of future space missions.

Recent spectacular advances by AI programs in 3D structure predictions from protein sequences have revolutionized the field in terms of accuracy and speed. The resulting “folding frenzy” has already produced predicted protein structure databases for the entire human and other organisms’ proteomes. However, rapidly ascertaining a predicted structure’s reliability based on measured properties in solution should be considered. Shape-sensitive hydrodynamic parameters such as the diffusion and sedimentation coefficients ( D t ( 20 , w ) 0 , s 20 , w 0 ) and the intrinsic viscosity ([ η ]) can provide a rapid assessment of the overall structure likeliness, and SAXS would yield the structure-related pair-wise distance distribution function p ( r ) vs. r . Using the extensively validated UltraScan SOlution MOdeler (US-SOMO) suite, a database was implemented calculating from AlphaFold structures the corresponding D t ( 20 , w ) 0 , s 20 , w 0 , [ η ], p ( r ) vs. r , and other parameters. Circular dichroism spectra were computed using the SESCA program. Some of AlphaFold’s drawbacks were mitigated, such as generating whenever possible a protein’s mature form. Others, like the AlphaFold direct applicability to single-chain structures only, the absence of prosthetic groups, or flexibility issues, are discussed. Overall, this implementation of the US-SOMO-AF database should already aid in rapidly evaluating the consistency in solution of a relevant portion of AlphaFold predicted protein structures.

Cobamides such as vitamin B12 are structurally conserved, cobalt-containing tetrapyrrole biomolecules that have essential biochemical functions in all domains of life. In organohalide respiration, a vital biological process for the global cycling of natural and anthropogenic organohalogens, cobamides are the requisite prosthetic groups for carbon-halogen bond-cleaving reductive dehalogenases. This study reports the biosynthesis of a new cobamide with unsubstituted purine as the lower base and assigns unsubstituted purine a biological function by demonstrating that Coα-purinyl-cobamide (purinyl-Cba) is the native prosthetic group in catalytically active tetrachloroethene reductive dehalogenases of Desulfitobacterium hafniense. Cobamides featuring different lower bases are not functionally equivalent, and purinyl-Cba elicits different physiological responses in corrinoid-auxotrophic, organohalide-respiring bacteria. Given that cobamide-dependent enzymes catalyze key steps in essential metabolic pathways, the discovery of a novel cobamide structure and the realization that lower bases can effectively modulate enzyme activities generate opportunities to manipulate functionalities of microbiomes.

Radiolabeling of biomolecules and cells with radiolabeled prosthetic groups has significant implications for nuclear medicine, imaging, and radiotherapy. Achieving site-specific and controlled incorporation of radiolabeled prostheses under mild reaction conditions is crucial for minimizing the impact on the bioactivity of the radiolabeled compounds. The targeting of natural and abundant amino acids during radiolabeling of biomolecules often results in nonspecific and uncontrolled modifications. Cysteine is distinguished by its low natural abundance and unique nucleophilicity. It is therefore an optimal target for site-selective and site-specific radiolabeling of biomolecules under controlled parameters. This review extensively discusses thiol-specific radiolabeled prosthetic groups and provides a critical analysis and comprehensive study of the synthesis of these groups, their and stability profiles, reaction kinetics, stability of resulting adducts, and overall impact on the targeting ability of radiolabeled biomolecules. The insights presented here aim to facilitate the development of highly efficient radiopharmaceuticals, initially in preclinical settings and ultimately in clinical applications.