Rational redesign of the loop dynamics of carbonyl reductase LfSDR1 to improve the stereoselectivity for asymmetric synthesis of bulky chiral alcohols.

Engineering biocatalysts with enhanced stereoselectivity is highly desirable, and active-site loop dynamics play an important role in its regulation. However, knowledge of their precise roles in catalysis and evolution is limited. Here, we used the strategy of Rosetta enzyme design combined molecular dynamic simulations (MDs) to reprogram the landscapes of the key active-site loop dynamics of the carbonyl reductase LfSDR1 to improve stereoselectivity.

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood.

PBX3 promotes pentose phosphate pathway and colorectal cancer progression by enhancing G6PD expression.

Metabolic reprogramming is a hallmark of cancers crucial for fulfilling the needs of energy, building blocks, and antioxidants to support tumor cells' rapid proliferation and to cope with the harsh microenvironment. Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family whose expression is up-regulated in various tumors, however, whether it is involved in tumor cell metabolic reprogramming remains unclear. Herein, we report that PBX3 is a positive regulator of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP).

YY2/PHGDH axis suppresses tumorigenesis by inhibiting tumor cell de novo serine biosynthesis.

Metabolic reprogramming is one of the key features of tumors facilitating their rapid proliferation and adaptation to harsh microenvironments. Yin Yang 2 (YY2) has recently been reported as a tumor suppressor downregulated in various types of tumors; however, the molecular mechanisms underlying its tumor-suppressive activity remain poorly understood. Furthermore, the involvement of YY2 in tumor cell metabolic reprogramming remains unclear.

YY2-DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division.

Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application.

Mechanosensitive Ion Channel PIEZO1 Signaling in the Hall-Marks of Cancer: Structure and Functions.

Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties.

Unspliced XBP1 contributes to cholesterol biosynthesis and tumorigenesis by stabilizing SREBP2 in hepatocellular carcinoma.

Cholesterol biosynthesis plays a critical role in rapidly proliferating tumor cells. X-box binding protein 1 (XBP1), which was first characterized as a basic leucine zipper-type transcription factor, exists in an unspliced (XBP1-u) and spliced (XBP1-s) form. Recent studies showed that unspliced XBP1 (XBP1-u) has unique biological functions independent from XBP1-s and could promote tumorigenesis; however, whether it is involved in tumor metabolic reprogramming remains unknown.

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells.

Homeostasis Imbalance of YY2 and YY1 Promotes Tumor Growth by Manipulating Ferroptosis.

Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are highly homologous, especially in their zinc-finger domains. Furthermore, they share a consensus DNA binding motif.

Novel Insights into the Inhibitory Effect and Mechanism of Proanthocyanidins from Pyracantha fortuneana Fruit on α-Glucosidase.

Unlabelled: Proanthocyanidins were extracted from Pyracantha fortuneana fruit (PFF), and their structures were investigated through C nuclear magnetic resonance ( C NMR), high performance liquid chromatography (HPLC) and high resolution mass spectrometry (HRMS). The results showed that these compounds were predominantly constituted of procyanidin with A-type and B-type linkage and coexistence of procyanidins glucoside. Spectroscopy methods were used to analyze the inhibitory activity of proanthocyanidins on α-glucosidase.

Quinazolinone derivatives: Synthesis and comparison of inhibitory mechanisms on α-glucosidase.

In this study, eight quinazolinone derivatives were designed and synthesized. Their inhibitory activities on α-glucosidase were assessed in vitro. Two compounds: 2-(4-chlorophenyl)-quinazolin-4(3H)-one (CQ) and 2-(4-bromophenyl)-quinazolin-4(3H)-one (BQ) were found to be potent inhibitors of α-glucosidase with IC values of 12.

2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor: Synthesis, inhibitory activity, and mechanism.

2-(4-Fluorophenyl)-quinazolin-4(3H)-one (FQ) was synthesized, and its structure was identified with (1)H nuclear magnetic resonance ((1)H NMR), (13)C nuclear magnetic resonance ((13)C NMR), fourier transform infrared spectroscopy (FTIR), and high resolution mass spectrometry (HRMS). From the enzyme analysis, the results showed that it could inhibit the diphenolase activity of tyrosinase (IC50=120±2μM). Furthermore, the results of kinetic studies showed that the compound was a reversible mixed-type inhibitor, and that the inhibition constants were determined to be 703.

Proanthocyanidins Extracted from Rhododendron pulchrum Leaves as Source of Tyrosinase Inhibitors: Structure, Activity, and Mechanism.

The objective of this study was to assess the structure, anti-tyrosinase activity, and mechanism of proanthocyanidins extracted from Rhododendron pulchrum leaves. Results obtained from mass spectra of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS) revealed that proanthocyanidins were complex mixtures of procyanidins, prodelphinidins, propelargonidins, and their derivatives, among which procyanidins were the main components. The anti-tyrosinase analysis results indicated that the mixtures were reversible and mixed competitive inhibitors of tyrosinase.

Avocado Proanthocyanidins as a Source of Tyrosinase Inhibitors: Structure Characterization, Inhibitory Activity, and Mechanism.

Proanthocyanidins were purified from avocado (Persea americana) fruit, and their structures were analyzed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and high-performance liquid chromatography-electrospray ionization-QTRAP mass spectrometry (HPLC-ESI-QTRAP MS) techniques. The results obtained from mass spectrometry (MS) analysis demonstrated that the proanthocyanidins were homo- and heteropolymers of procyanidins, prodelphinidins, propelargonidins, and procyanidin gallate. From the enzyme analysis, the results showed that they could inhibit the monophenolase and diphenolase activities of tyrosinase.