0
selected
-
1.
Enzymatic Oxidation of Tea Catechins and Its Mechanism.
Abudureheman, B, Yu, X, Fang, D, Zhang, H
Molecules (Basel, Switzerland). 2022;(3)
Abstract
Tea (Camellia sinensis, Theaceae) is one of the most widely consumed beverages in the world. The three major types of tea, green tea, oolong tea, and black tea, differ in terms of the manufacture and chemical composition. Catechins, theaflavins, and thearubigins have been identified as the major components in tea. Other minor oligomers have also been found in tea. Different kinds of ring fission and formation elucidate the major transformed pathways of tea catechins to their dimers and polymers. The present review summarizes the data concerning the enzymatic oxidation of catechins, their dimers, and thearubigins in tea.
-
2.
Chemoenzymatic Total Synthesis of Natural Products.
Chakrabarty, S, Romero, EO, Pyser, JB, Yazarians, JA, Narayan, ARH
Accounts of chemical research. 2021;(6):1374-1384
-
-
Free full text
-
Abstract
The total synthesis of structurally complex natural products has challenged and inspired generations of chemists and remains an exciting area of active research. Despite their history as privileged bioactivity-rich scaffolds, the use of natural products in drug discovery has waned. This shift is driven by their relatively low abundance hindering isolation from natural sources and the challenges presented by their synthesis. Recent developments in biocatalysis have resulted in the application of enzymes for the construction of complex molecules. From the inception of the Narayan lab in 2015, we have focused on harnessing the exquisite selectivity of enzymes alongside contemporary small molecule-based approaches to enable concise chemoenzymatic routes to natural products.We have focused on enzymes from various families that perform selective oxidation reactions. For example, we have targeted xyloketal natural products through a strategy that relies on a chemo- and site-selective biocatalytic hydroxylation. Members of the xyloketal family are characterized by polycyclic ketal cores and demonstrate potent neurological activity. We envisioned assembling a representative xyloketal natural product (xyloketal D) involving a biocatalytically generated ortho-quinone methide intermediate. The non-heme iron (NHI) dependent monooxygenase ClaD was used to perform the benzylic hydroxylation of a resorcinol precursor, the product of which can undergo spontaneous loss of water to form an ortho-quinone methide under mild conditions. This intermediate was trapped using a chiral dienophile to complete the total synthesis of xyloketal D.A second class of biocatalytic oxidation that we have employed in synthesis is the hydroxylative dearomatization of resorcinol compounds using flavin-dependent monooxygenases (FDMOs). We anticipated that the catalyst-controlled site- and stereoselectivity of FDMOs would enable the total synthesis of azaphilone natural products. Azaphilones are bioactive compounds characterized by a pyranoquinone bicyclic core and a fully substituted chiral carbon atom. We leveraged the stereodivergent reactivity of FDMOs AzaH and AfoD to achieve the enantioselective synthesis of trichoflectin enantiomers, deflectin 1a, and lunatoic acid. We also leveraged FDMOs to construct tropolone and sorbicillinoid natural products. Tropolones are a structurally diverse class of bioactive molecules characterized by an aromatic cycloheptatriene core bearing an α-hydroxyketone moiety. We developed a two-step biocatalytic cascade to the tropolone natural product stipitatic aldehyde using the FDMO TropB and a NHI monooxygenase TropC. The FDMO SorbC obtained from the sorbicillin biosynthetic pathway was used in the concise total synthesis of a urea sorbicillinoid natural product.Our long-standing interest in using enzymes to carry out C-H hydroxylation reactions has also been channeled for the late-stage diversification of complex scaffolds. For example, we have used Rieske oxygenases to hydroxylate the tricyclic core common to paralytic shellfish toxins. The systemic toxicity of these compounds can be reduced by adding hydroxyl and sulfate groups, which improves their properties and potential as therapeutic agents. The enzymes SxtT, GxtA, SxtN, and SxtSUL were used to carry out selective C-H hydroxylation and O-sulfation in saxitoxin and related structures. We conclude this Account with a discussion of existing challenges in biocatalysis and ways we can currently address them.
-
3.
Towards a Synthetic Biology Toolset for Metallocluster Enzymes in Biosynthetic Pathways: What We Know and What We Need.
Shomar, H, Bokinsky, G
Molecules (Basel, Switzerland). 2021;(22)
Abstract
Microbes are routinely engineered to synthesize high-value chemicals from renewable materials through synthetic biology and metabolic engineering. Microbial biosynthesis often relies on expression of heterologous biosynthetic pathways, i.e., enzymes transplanted from foreign organisms. Metallocluster enzymes are one of the most ubiquitous family of enzymes involved in natural product biosynthesis and are of great biotechnological importance. However, the functional expression of recombinant metallocluster enzymes in live cells is often challenging and represents a major bottleneck. The activity of metallocluster enzymes requires essential supporting pathways, involved in protein maturation, electron supply, and/or enzyme stability. Proper function of these supporting pathways involves specific protein-protein interactions that remain poorly characterized and are often overlooked by traditional synthetic biology approaches. Consequently, engineering approaches that focus on enzymatic expression and carbon flux alone often overlook the particular needs of metallocluster enzymes. This review highlights the biotechnological relevance of metallocluster enzymes and discusses novel synthetic biology strategies to advance their industrial application, with a particular focus on iron-sulfur cluster enzymes. Strategies to enable functional heterologous expression and enhance recombinant metallocluster enzyme activity in industrial hosts include: (1) optimizing specific maturation pathways; (2) improving catalytic stability; and (3) enhancing electron transfer. In addition, we suggest future directions for developing microbial cell factories that rely on metallocluster enzyme catalysis.
-
4.
The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction.
Sergi, D, Boulestin, H, Campbell, FM, Williams, LM
Molecular nutrition & food research. 2021;(1):e1900934
Abstract
Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non-enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β-cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β-cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.
-
5.
The evolving capabilities of enzyme-mediated proximity labeling.
Zhou, Y, Zou, P
Current opinion in chemical biology. 2021;:30-38
Abstract
The subcellular organization of proteins and RNA molecules is crucial for their proper functions. Over the past decade, both ligase-mediated and peroxidase-mediated proximity labeling (PL) techniques have been developed to map biomolecules at near-nanometer spatial resolution and subminute temporal resolution. These methods are shedding light on the spatial arrangement of proteome and transcriptome in their native context. Here, we review the recent evolution and applications of PL techniques, compare and contrast the two classes of methods, and highlight emerging trends and future opportunities.
-
6.
Microbial production of value-added bioproducts and enzymes from molasses, a by-product of sugar industry.
Zhang, S, Wang, J, Jiang, H
Food chemistry. 2021;:128860
Abstract
Molasses is a major by-product of sugar industry and contains 40-60% (w/w) of sugars. The world's annual yield of molasses reaches 55 million tons. Traditionally, molasses is simply discharged or applied to feed production. Additionally, some low-cost and environmentally friendly bioprocesses have been established for microbial production of value-added bioproducts from molasses. Over the last decade and more, increasing numbers of biofuels, polysaccharides, oligosaccharides, organic acids, and enzymes have been produced from the molasses through microbial conversion that possess an array of important applications in the industries of food, energy, and pharmaceutical. For better application, it is necessary to comprehensively understand the research status of bioconversion of molasses that has not been elaborated in detail so far. In this review, these value-added bioproducts and enzymes obtained through bioconversion of molasses, their potential applications in food and other industries, as well as the future research focus were generalized and discussed.
-
7.
Interchangeable utilization of metals: New perspectives on the impacts of metal ions employed in ancient and extant biomolecules.
Smethurst, DGJ, Shcherbik, N
The Journal of biological chemistry. 2021;(6):101374
Abstract
Metal ions provide considerable functionality across biological systems, and their utilization within biomolecules has adapted through changes in the chemical environment to maintain the activity they facilitate. While ancient earth's atmosphere was rich in iron and manganese and low in oxygen, periods of atmospheric oxygenation significantly altered the availability of certain metal ions, resulting in ion replacement within biomolecules. This adaptation mechanism has given rise to the phenomenon of metal cofactor interchangeability, whereby contemporary proteins and nucleic acids interact with multiple metal ions interchangeably, with different coordinated metals influencing biological activity, stability, and toxic potential. The ability of extant organisms to adapt to fluctuating metal availability remains relevant in a number of crucial biomolecules, including the superoxide dismutases of the antioxidant defense systems and ribonucleotide reductases. These well-studied and ancient enzymes illustrate the potential for metal interchangeability and adaptive utilization. More recently, the ribosome has also been demonstrated to exhibit interchangeable interactions with metal ions with impacts on function, stability, and stress adaptation. Using these and other examples, here we review the biological significance of interchangeable metal ions from a new angle that combines both biochemical and evolutionary viewpoints. The geochemical pressures and chemical properties that underlie biological metal utilization are discussed in the context of their impact on modern disease states and treatments.
-
8.
Zinc enzymes in medicinal chemistry.
Hou, R, He, Y, Yan, G, Hou, S, Xie, Z, Liao, C
European journal of medicinal chemistry. 2021;:113877
Abstract
In humans, more than three hundred diverse enzymes that require zinc as an essential cofactor have been identified. These zinc enzymes have demonstrated different and important physiological functions and some of them have been considered as valuable therapeutic targets for drug discovery. Indeed, many drugs targeting a few zinc enzymes have been marketed to treat a variety of diseases. This review discusses drug discovery and drug development based on a dozen of zinc enzymes, including their biological functions and pathogenic roles, their best in class inhibitors (and clinical trial data when available), coordination and binding modes of representative inhibitors, and their implications for further drug design. The opportunities and challenges in developing zinc enzyme inhibitors for the treatment of human disorders are highlighted, too.
-
9.
A review on mechanistic aspects of individual versus combined uses of enzymes as clean label-friendly dough conditioners in breads.
Dai, Y, Tyl, C
Journal of food science. 2021;(5):1583-1598
Abstract
Numerous dough improvers are used alone or in combination to enhance the quality of baked goods such as breads. While modern consumers demand consistent quality, the expectations for ingredients have changed over the past few years, and reformulations have taken place to provide "clean label" options. However, the effects and mechanisms of blended dough conditioners suitable for such baked products have not been systematically summarized. In this review, dough and bread properties as affected by different improver combinations are examined, with a focus on additive or synergistic interactions between enzymes or between enzymes and ascorbic acid. The combination of enzymes that hydrolyze starch and cell wall polysaccharides has been shown to reduce textural hardness in fresh and stored bakes goods such as breads. Enzymes that hydrolyze arabinoxylans, the main nonstarch polysaccharide in wheat, have synergistic effects with enzymes that result in cross-linking of wheat flour biopolymers. In some studies, the effects of bread improvers varied for wheat flours of different strength. Overall, bread products in which wheat is used in whole grain form or in a blend with other flours especially benefit from multiple improvers that target different flour constituents in doughs.
-
10.
Biosynthetic pathways and enzymes involved in the production of phosphonic acid natural products.
Shiraishi, T, Kuzuyama, T
Bioscience, biotechnology, and biochemistry. 2021;(1):42-52
Abstract
Phosphonates are organophosphorus compounds possessing a characteristic C-P bond in which phosphorus is directly bonded to carbon. As phosphonates mimic the phosphates and carboxylates of biological molecules to potentially inhibit metabolic enzymes, they could be lead compounds for the development of a variety of drugs. Fosfomycin (FM) is a representative phosphonate natural product that is widely used as an antibacterial drug. Here, we review the biosynthesis of FM, which includes a recent breakthrough to find a missing link in the biosynthetic pathway that had been a mystery for a quarter-century. In addition, we describe the genome mining of phosphonate natural products using the biosynthetic gene encoding an enzyme that catalyzes C-P bond formation. We also introduce the chemoenzymatic synthesis of phosphonate derivatives. These studies expand the repertoires of phosphonates and the related biosynthetic machinery. This review mainly covers the years 2012-2020.