Publications by authors named "Pedro A Fernandes"

Snake venom-secreted phospholipases A (svPLAs) are critical, highly toxic enzymes present in almost all snake venoms. Upon snakebite envenomation, svPLAs hydrolyze cell membrane phospholipids and induce pathological effects such as paralysis, myonecrosis, inflammation, or pain. Despite its central importance in envenomation, the chemical mechanism of svPLAs is poorly understood, with detrimental consequences for the design of small-molecule snakebite antidotes, which is highly undesirable given the gravity of the epidemiological data that ranks snakebite as the deadliest neglected tropical disease.

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Streptococcus mutans, a bacterium commonly found in the human oral cavity, is considered the primary causative agent of dental caries. A key player in the pathophysiology of S. mutans is SloR, a 25-kDa metalloregulatory protein.

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Global plastic production exceeded 400 million tons in 2022, urgently demanding improved waste management and recycling strategies for a circular plastic economy. While the enzymatic hydrolysis of polyethylene terephthalate (PET) has become feasible on industrial scales, efficient enzymes targeting other hydrolyzable plastic types, such as polyurethanes (PURs), are lacking. Recently, enzymes of the amidase signature (AS) family, capable of cleaving urethane bonds in a polyether-PUR analog and a linear polyester-PUR, have been identified.

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Snakebite envenoming claims 81-138 thousand lives annually, with vipers responsible for many of those. Phospholipase A (PLA) enzymes and PLA-like proteins are among the most important viper venom toxins. The latter are particularly intriguing, as three decades after their discovery, their molecular mechanism of toxicity is still poorly understood at best.

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Nucleic acid mimics (NAMs) have demonstrated high potential as antibacterial drugs. However, very few studies have assessed their possible diffusion across the bacterial envelope. In this work, we studied NAMs' diffusion in lipid bilayer systems that mimic the bacterial outer membrane using molecular dynamics (MD) simulations.

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Fatty acid synthase (FAS) multienzymes are responsible for de novo fatty acid biosynthesis and crucial in primary metabolism. Despite extensive research, the molecular details of the FAS catalytic mechanisms are still poorly understood. For example, the β-ketoacyl synthase (KS) catalyzes the fatty acid elongating carbon-carbon-bond formation, which is the key catalytic step in biosynthesis, but factors that determine the speed and accuracy of his reaction are still unclear.

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We have studied the hydroxylation mechanism of l-Tyr by the heme-dependent enzyme CYP76AD1 from the sugar beet (). This enzyme has a promising biotechnological application in modified yeast strains to produce medicinal alkaloids, an alternative to the traditional opium poppy harvest. A generative machine learning software based on AlphaFold was used to build the structure of CYP76AD1 since there are no structural data for this specific enzyme.

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Article Synopsis
  • "Purple Drank" is a drink combining promethazine and codeine, known for its hallucinogenic effects but can be dangerous in high doses.
  • The study investigated how these drugs bind to human serum albumin (HSA) using high-performance affinity chromatography, finding PMZ and its metabolites bind strongly to HSA while codeine has a lower binding affinity.
  • Displacement experiments and molecular docking indicated that all three compounds bind to HSA at both sites, with competition mainly between PMZ and codeine occurring at site II, and the binding wasn't affected by the chirality (enantiomers).
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Secreted phospholipase A2 (sPLA2) is a Ca-dependent, widely distributed enzyme superfamily in almost all mammalian tissues and bacteria. It is also a critical component of the venom of nearly all snakes, as well as many invertebrate species. In non-venomous contexts, sPLA2 assumes significance in cellular signaling pathways by binding cell membranes and catalyzing ester bond hydrolysis at the sn-2 position of phospholipids.

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Trypsin is a serine protease, an important digestive enzyme that digests the proteins in the small intestine. In the present study, we have investigated the interaction of safranal, a major saffron metabolite, with trypsin using spectroscopic and molecular docking analyses. Fluorescence emission spectra of trypsin were largely affected by the inner filter effect from safranal; that's why these were corrected using the standard procedure.

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Article Synopsis
  • Regulations require ultralow sulfur levels in fossil fuels, especially diesel, due to health and environmental concerns, but current desulfurization methods are costly and ineffective against certain sulfur compounds.
  • Biodesulfurization using the 4S pathway from a specific bacterium offers a potential solution, although its enzymes, particularly DszA, need to work significantly faster for practical industrial use.
  • This research uncovers the unique catalytic mechanism of the enzyme DszA, revealing a specific chemical process that could aid in improving its efficiency, making biodesulfurization a more viable option for the oil refining sector.*
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Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization's list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2-2.5 million new cases appearing every year.

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Article Synopsis
  • Viper venom contains phospholipase A2 enzymes (vvPLA2s) and PLA2-like proteins that cause severe muscle and nerve damage during snakebites, which is a major neglected tropical disease.
  • A new database has been created featuring the 3D structures of 217 vvPLA2 and PLA2-like proteins, along with data on 79 viper species, to aid scientific research in developing anti-snakebite drugs.
  • This study not only examines the structure and toxicity mechanisms of these proteins but also suggests ways to develop effective inhibitors to combat their harmful effects across different viper species.
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Divalent metal ions are essential micronutrients for many intercellular reactions. Maintaining their homeostasis is necessary for the survival of bacteria. In Streptococcus gordonii, one of the primary colonizers of the tooth surface, the cellular concentration of manganese ions (Mn) is regulated by the manganese-sensing transcriptional factor ScaR which controls the expression of proteins involved in manganese homeostasis.

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Due to the emergence of antibiotic resistance, the need to explore novel antibiotics and/or novel strategies to counter antibiotic resistance is of utmost importance. In this work, we explored the molecular and mechanistic details of the degradation of a streptogramin B antibiotic by virginiamycin B (Vgb) lyase of using classical molecular dynamics simulations and multiscale quantum mechanics/molecular mechanics methods. Our results were in line with available experimental kinetic information.

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()-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with ()-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops.

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The fascination and fear of snakes dates back to time immemorial, with the first scientific treatise on snakebite envenoming, the Brooklyn Medical Papyrus, dating from ancient Egypt. Owing to their lethality, snakes have often been associated with images of perfidy, treachery and death. However, snakes did not always have such negative connotations.

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Snake venom metalloproteinases (SVMPs) are important drug targets against snakebite envenoming, the neglected tropical disease with the highest mortality worldwide. Here, we focus on Russell's viper (), one of the "big four" snakes of the Indian subcontinent that, together, are responsible for ca. 50,000 fatalities annually.

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Mitochondrial targeting represents an attractive strategy for treating metabolic, degenerative and hyperproliferative diseases, since this organelle plays key roles in essential cellular functions. Triphenylphosphonium (TPP) moieties - the current "gold standard" - have been widely used as mitochondrial targeting vectors for a wide range of molecular cargo. Recently, further optimisation of the TPP platform drew considerable interest as a way to enhance mitochondrial therapies.

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Animal venoms and their chemical compounds have aroused both empirical and scientific attention for ages. However, there has been a significant increase in scientific investigations in recent decades, allowing the production of various formulations that are helping in the development of many important tools for biotechnological, diagnostic, or therapeutic use, both in human and animal health, as well as in plants. Venoms are composed of biomolecules and inorganic compounds that may have physiological and pharmacological activities that are not related to their principal actions (prey immobilization, digestion, and defense).

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Snake venom-secreted phospholipase A (svPLA) enzymes, both catalytically active and inactive, are a central component in envenoming. These are responsible for disrupting the cell membrane's integrity, inducing a wide range of pharmacological effects, such as the necrosis of the bitten limb, cardiorespiratory arrest, edema, and anticoagulation. Although extensively characterized, the reaction mechanisms of enzymatic svPLA are still to be thoroughly understood.

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Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures-there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential.

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We describe an approach to identify enzyme mutants with increased turnover using the enzyme DszC as a case study. Our approach is based on recalculating the barriers of alanine mutants through single-point energy calculations at the hybrid QM/MM level in the wild-type reactant and transition state geometries. We analyze the difference in the electron density between the reactant and transition state to identify sites/residues where electrostatic interactions stabilize the transition state over the reactants.

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