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Various traditional Chinese herbs and complex formulas have been suggested to exhibit lifespan extension properties. Here, the authors isolated the flavonoid corylin from Psoralea corylifolia and demonstrated its longevity properties in yeast, human cells and mouse.

Pathogenic IgA1 metalloproteases block the initial host immune response by cleaving host IgA1. Using cryoEM, the authors here provide structural insights into the substrate recognition mechanism of Streptococcus pneumoniae IgA1 protease, and develop a protease-inhibiting antibody.

Abstract C2′-halogenation has been recognized as an essential modification to enhance the drug-like properties of nucleotide analogs. The direct C2ʹ-halogenation of the nucleotide 2′-deoxyadenosine-5′-monophosphate (dAMP) has recently been achieved using the Fe(II)/α-ketoglutarate-dependent nucleotide halogenase AdaV. However, the limited substrate scope of this enzyme hampers its broader applications. In this study, we report two halogenases capable of halogenating 2ʹ-deoxyguanosine monophosphate (dGMP), thereby expanding the family of nucleotide halogenases. Computational studies reveal that nucleotide specificity is regulated by the binding pose of the phosphate group. Based on these findings, we successfully engineered the substrate specificity of these halogenases by mutating second-sphere residues. This work expands the toolbox of nucleotide halogenases and provides insights into the regulation mechanism of nucleotide specificity.

The emergence of drug resistance among pathogens has become a major challenge to human health on a global scale. Among them, antibiotic resistance is already a critical issue, and finding new therapeutic agents to address this problem is therefore urgent. One of the most promising alternatives to antibiotics are antibacterial peptides (ABPs), i.e., short peptides with antibacterial activity. In this study, we propose a novel ABP recognition method, called ABPCaps. It integrates a convolutional neural network (CNN), a long short-term memory (LSTM), and a new type of neural network named the capsule network. The capsule network can extract critical features automatically from both positive and negative samples, leading to superior performance of ABPCaps over all baseline models built on hand-crafted peptide descriptors. Evaluated on independent test sets, ABPCaps achieves an accuracy of 93.33% and an F1-score of 91.34%, and consistently outperforms the baseline models in other extensive experiments as well. Our study demonstrates that the proposed ABPCaps, built on the capsule network method, is a valuable addition to the current state-of-the-art in the field of ABP recognition and has significant potential for further development.

Steroid 5α-reductase 2 (SRD5A2), a testosterone metabolism enzyme, is implicated in human disease. Structural and biochemical analyses of PbSRD5A, a bacterial homolog, reveal SRD5A2 substrate binding pocket and provide framework for the design of new drugs targeting this enzyme.

Cytochrome P450 17A1 (CYP17A1) is one of the key enzymes in steroidogenesis that produces dehydroepiandrosterone (DHEA) from cholesterol. Abnormal DHEA production may lead to the progression of severe diseases, such as prostatic and breast cancers. Thus, CYP17A1 is a druggable target for anti-cancer molecule development. In this study, cheminformatic analyses and quantitative structure–activity relationship (QSAR) modeling were applied on a set of 962 CYP17A1 inhibitors (i.e., consisting of 279 steroidal and 683 nonsteroidal inhibitors) compiled from the ChEMBL database. For steroidal inhibitors, a QSAR classification model built using the PubChem fingerprint along with the extra trees algorithm achieved the best performance, reflected by the accuracy values of 0.933, 0.818, and 0.833 for the training, cross-validation, and test sets, respectively. For nonsteroidal inhibitors, a systematic cheminformatic analysis was applied for exploring the chemical space, Murcko scaffolds, and structure–activity relationships (SARs) for visualizing distributions, patterns, and representative scaffolds for drug discoveries. Furthermore, seven total QSAR classification models were established based on the nonsteroidal scaffolds, and two activity cliff (AC) generators were identified. The best performing model out of these seven was model VIII, which is built upon the PubChem fingerprint along with the random forest algorithm. It achieved a robust accuracy across the training set, the cross-validation set, and the test set, i.e., 0.96, 0.92, and 0.913, respectively. It is anticipated that the results presented herein would be instrumental for further CYP17A1 inhibitor drug discovery efforts.

α-Synuclein (αSyn) aggregation is involved in the pathogenesis of Parkinson disease (PD). Recently, substitution of histidine 50 in αSyn with a glutamine, H50Q, was identified as a new familial PD mutant. Here, nuclear magnetic resonance (NMR) studies revealed that the H50Q substitution causes an increase of the flexibility of the C-terminal region. This finding provides direct evidence that this PD-causing mutant can mediate long range effects on the sampling of αSyn conformations. In vitro aggregation assays showed that substitution of His-50 with Gln, Asp, or Ala promotes αSyn aggregation, whereas substitution with the positively charged Arg suppresses αSyn aggregation. Histidine carries a partial positive charge at neutral pH, and so our result suggests that positively charged His-50 plays a role in protecting αSyn from aggregation under physiological conditions. [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP)-MgCl[sub2] attenuates ischemia-reperfusion (I-R)-induced lung injury in rats. A previous study indirectly suggests that Mg[sup2+]-dependent ecto-ATPases on the surface of leukocytes are responsible for the hydrolysis of ATP-MgCl[sub2] to adenosine, which then contributes to the protective effect of ATP-MgCl[sub2]. This study investigated the role of leukocytes in I-R injury and the protective effect of ATP-MgCl[sub2] in our buffer-perfused isolated rat lung model. After isolating the lung blood flow of adult male Sprague-Dawley rats, the lungs were perfused through the pulmonary artery cannula with a physiologic salt solution containing human serum albumin. The protective effect of ATP-MgCl[sub2] pretreatment with or without leukocytes was investigated. Capillary permeability (K[subfc]), lung weight gain (LWG), lung wet weight/body weight ratio (LW/BW), lung lavage protein concentration (LPC) and pulmonary artery pressure (PAP) were measured. I-R produced a significant increase in K[subfc], LWG, LW/BW, LPC, and PAP. The increases in these indices were significantly attenuated by pretreatment with ATP-MgCl[sub2] (1 x 10[sup-6] M) together with leukocytes (2.9 x 10[sup6]/ml in the perfusate) but not with ATP-MgCl[sub2] alone. Our data suggest that I-R-induced acute lung injury is not dependent on circulating leukocytes. Pretreatment with ATP-MgCl[sub2] plus leukocytes but not ATP-MgCl[sub2] alone had protective effects against I-R lung injury. Whether these findings occur in vivo could not be determined in this study. In our isolated lung red blood cell-free perfusate system, the protective effect of ATP-MgCl[sub2] requires the presence of leukocytes. Copyright ? 2003 National Science Council, ROC and S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

Substrate permissiveness has long been regarded as the raw materials for the evolution of new enzymatic functions. In land plants, hydroxycinnamoyltransferase (HCT) is an essential enzyme of the phenylpropanoid metabolism. Although essential enzymes are normally associated with high substrate specificity, HCT can utilize a variety of non-native substrates. To examine the structural and dynamic basis of substrate permissiveness in this enzyme, we report the crystal structure of HCT from Selaginella moellendorffii and molecular dynamics (MD) simulations performed on five orthologous HCTs from several major lineages of land plants. Through altogether 17-μs MD simulations, we demonstrate the prevalent swing motion of an arginine handle on a submicrosecond timescale across all five HCTs, which plays a key role in native substrate recognition by these intrinsically promiscuous enzymes. Our simulations further reveal how a non-native substrate of HCT engages a binding site different from that of the native substrate and diffuses to reach the catalytic center and its co-substrate. By numerically solving the Smoluchowski equation, we show that the presence of such an alternative binding site, even when it is distant from the catalytic center, always increases the reaction rate of a given substrate. However, this increase is only significant for enzyme-substrate reactions heavily influenced by diffusion. In these cases, binding non-native substrates 'off-center' provides an effective rationale to develop substrate permissiveness while maintaining the native functions of promiscuous enzymes.