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Current Opinion in Chemical Biology

Michael J Fink, Per-Olof Syrén
Herein we highlight recent findings on the importance of water networks in proteins, and their redesign and reconfiguration as a new engineering strategy to generate enzymes with modulated binding affinity and improved catalytic versatility. Traditionally, enzyme engineering and drug design have focused on tailoring direct and favorable interactions between protein surfaces and ligands/transition states to achieve stronger binding, or an accelerated manufacturing of medicines, biofuels, fine chemicals and materials...
March 18, 2017: Current Opinion in Chemical Biology
Richard Obexer, Louise J Walport, Hiroaki Suga
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable...
March 17, 2017: Current Opinion in Chemical Biology
Justin M Bradley, Geoffrey R Moore, Nick E Le Brun
The essential metal iron presents two major problems for life: it is potentially highly toxic due to its redox activity, and its extremely low solubility in aqueous solution in the presence of O2 can make it hard to acquire and store safely. Ferritins are part of nature's answer to these problems, as they store iron in a safe but accessible form in all types of cells. How they achieve this has been the subject of intense research for several decades. Here, we highlight recent progress in elucidating the routes by which Fe(2+) ions access the catalytic ferroxidase centers, and the mechanisms by which Fe(2+) is oxidized...
March 14, 2017: Current Opinion in Chemical Biology
Ruma Banerjee
The view of enzymes as punctilious catalysts has been shifting as examples of their promiscuous behavior increase. However, unlike a number of cases where the physiological relevance of breached substrate specificity is questionable, the very synthesis of H2S relies on substrate and reaction promiscuity, which presents the enzymes with a multitude of substrate and reaction choices. The transsulfuration pathway, a major source of H2S, is inherently substrate-ambiguous. A heme-regulated switch embedded in the first enzyme in the pathway can help avert the stochastic production of cysteine versus H2S and control switching between metabolic tracks to meet cellular needs...
March 7, 2017: Current Opinion in Chemical Biology
Anatol Luther, Kerstin Moehle, Eric Chevalier, Glenn Dale, Daniel Obrecht
Fully synthetic medium-sized macrocyclic peptides mimicking the key β-hairpin and α-helical protein epitopes relevant in many protein-protein interactions have emerged as a novel class of drugs with the potential to fill an important gap between small molecules and proteins. Conformationally stabilized macrocyclic scaffolds represent ideal templates for medicinal chemists to incorporate bioactive peptide and protein pharmacophores in order to generate novel drugs to treat diseases with high unmet medical need...
March 5, 2017: Current Opinion in Chemical Biology
Kenton J Hetrick, Wilfred A van der Donk
In the past 15 years, the cost of sequencing a genome has plummeted. Consequently, the number of sequenced bacterial genomes has exponentially increased, and methods for natural product discovery have evolved rapidly to take advantage of the wealth of genomic data. This review highlights applications of genome mining software to compare and organize large-scale data sets and methods for identifying unique biosynthetic pathways amongst the thousands of ribosomally synthesized and post-translationally modified peptide (RiPP) gene clusters...
March 2, 2017: Current Opinion in Chemical Biology
Matthew R Bennett, Sarah A Shepherd, Victoria A Cronin, Jason Micklefield
S-adenosyl-L-methionine-dependent methyltransferses are ubiquitous in nature, methylating a vast range of small molecule metabolites, as well as biopolymers. This review covers the recent advances in the development of methyltransferase enzymes for synthetic applications, focusing on the methyltransferase catalyzed transformations with S-adenosyl methionine analogs, as well as non-native substrates. We discuss how metabolic engineering approaches have been used to enhance S-adenosyl methionine production in vivo...
March 2, 2017: Current Opinion in Chemical Biology
Ali Tavassoli
Cyclic peptide libraries have demonstrated significant potential when employed against challenging targets such as protein-protein interactions. While a variety of methods for library generation exist, genetically encoded libraries hold several advantages over their chemically synthesized counterparts; they are more readily accessible and allow straightforward hit deconvolution. One method for the intracellular generation of such libraries is split-intein circular ligation of peptides and proteins (SICLOPPS)...
February 28, 2017: Current Opinion in Chemical Biology
David J Craik, Junqiao Du
Cyclotides are ultra-stable peptides derived from plants. They are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot. Their exceptional stability and tolerance to sequence substitutions has led to their use as frameworks in drug design. This article describes recent developments in this field, particularly developments over the last two years relating to the grafting of bioactive peptide sequences into the cyclic cystine knot framework of cyclotides to stabilize the sequences...
February 26, 2017: Current Opinion in Chemical Biology
Alessandro Zorzi, Kaycie Deyle, Christian Heinis
Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for the development of therapeutics. Over 40 cyclic peptide drugs are currently in clinical use and around one new cyclic peptide drug enters the market every year on average. The vast majority of clinically approved cyclic peptides are derived from natural products, such as antimicrobials or human peptide hormones. New powerful techniques based on rational design and in vitro evolution have enabled the de novo development of cyclic peptide ligands to targets for which nature does not offer solutions...
February 26, 2017: Current Opinion in Chemical Biology
Maximilian Ccjc Ebert, Joelle N Pelletier
This review presents computational methods that experimentalists can readily use to create smart libraries for enzyme engineering and to obtain insights into protein-substrate complexes. Computational tools have the reputation of being hard to use and inaccurate compared to experimental methods in enzyme engineering, yet they are essential to probe datasets of ever-increasing size and complexity. In recent years, bioinformatics groups have made a huge leap forward in providing user-friendly interfaces and accurate algorithms for experimentalists...
February 21, 2017: Current Opinion in Chemical Biology
Bei Zhang, Balamurugan Shanmugaraj, Henry Daniell
After approval of the first plant-made biopharmaceutical by FDA for human use, many protein drugs are now in clinical development. Within the last decade, significant advances have been made in expression of heterologous complex/large proteins in chloroplasts of edible plants using codon optimized human or viral genes. Furthermore, advances in quantification enable determination of in-planta drug dosage. Oral delivery of plastid-made biopharmaceuticals (PMB) is affordable because it eliminates prohibitively expensive fermentation, purification processes addressing major challenges of short shelf-life after cold storage...
February 21, 2017: Current Opinion in Chemical Biology
Marcel Schmidt, Ana Toplak, Peter Jlm Quaedflieg, Timo Nuijens
With the steadily increasing complexity and quantity requirements for peptides in industry and academia, the efficient and site-selective ligation of peptides and proteins represents a highly desirable goal. Within this context, enzyme-mediated ligation technologies for peptides and proteins have attracted great interest in recent years as they represent an extremely powerful extension to the scope of chemical methodologies (e.g. native chemical ligation) in basic and applied research. Compared to chemical ligation methods, enzymatic strategies using ligases such as sortase, butelase, peptiligase or omniligase generally feature excellent chemoselectivity, therefore making them valuable tools for protein and peptide chemists...
February 18, 2017: Current Opinion in Chemical Biology
Soham Mandal, Jens Müller
Nucleic acids such as DNA are increasingly being applied in nanotechnology, as a result of their capability to self-assemble reversibly. The formal replacement of canonical base pairs by metal-mediated ones enables a site-specific introduction of metal-based functionality into these biomolecules, leading to the formation of predesigned metal arrays. This article offers an overview of structural aspects of metal-mediated base pairs, reviews recent advances in the field of metal-mediated base pairing and presents potential applications of the resulting metal-modified nucleic acids...
February 17, 2017: Current Opinion in Chemical Biology
Conor J Zeer-Wanklyn, Deborah B Zamble
Nickel enzymes allow microorganisms to access chemistry that can be vital for survival and virulence. In this review we highlight recent work on several systems that import nickel ions and deliver them to the active sites of these enzymes. Small molecules, in particular l-His and derivatives, may chelate nickel ions before import at TonB-dependent outer-membrane and ABC-type inner-membrane transporters. Inside the cell, nickel ions are used by maturation factors required to produce nickel enzymes such as [NiFe]-hydrogenase, urease and lactate racemase...
February 16, 2017: Current Opinion in Chemical Biology
Jennifer Bridwell-Rabb, Catherine L Drennan
The ability of cobalamin to coordinate different upper axial ligands gives rise to a diversity of reactivity. Traditionally, adenosylcobalamin is associated with radical-based rearrangements, and methylcobalamin with methyl cation transfers. Recently, however, a new role for adenosylcobalamin has been discovered as a light sensor, and a methylcobalamin-dependent enzyme has been identified that is suggested to transfer a methyl anion. Additionally, recent studies have provided a wealth of new information about a third class of cobalamin-dependent enzymes that do not appear to use an upper ligand...
February 3, 2017: Current Opinion in Chemical Biology
Tobias J Erb, Patrik R Jones, Arren Bar-Even
Metabolic engineering aims at modifying the endogenous metabolic network of an organism to harness it for a useful biotechnological task, for example, production of a value-added compound. Several levels of metabolic engineering can be defined and are the topic of this review. Basic 'copy, paste and fine-tuning' approaches are limited to the structure of naturally existing pathways. 'Mix and match' approaches freely recombine the repertoire of existing enzymes to create synthetic metabolic networks that are able to outcompete naturally evolved pathways or redirect flux toward non-natural products...
January 30, 2017: Current Opinion in Chemical Biology
David M Upp, Jared C Lewis
Catalytic CH bond functionalization has become an important tool for organic synthesis. Metalloenzymes offer a solution to one of the foremost challenges in this field, site-selective CH functionalization, but they are only capable of catalyzing a subset of the CH functionalization reactions known to small molecule catalysts. To overcome this limitation, metalloenzymes have been repurposed by exploiting the reactivity of their native cofactors toward substrates not found in nature. Additionally, new reactivity has been accessed by incorporating synthetic metal cofactors into protein scaffolds to form artificial metalloenzymes...
January 27, 2017: Current Opinion in Chemical Biology
Maria João Romão, Catarina Coelho, Teresa Santos-Silva, Alessandro Foti, Mineko Terao, Enrico Garattini, Silke Leimkühler
Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism...
January 23, 2017: Current Opinion in Chemical Biology
Claire L Windle, Alan Berry, Adam Nelson
The introduction of fluorine has been widely exploited to tune the biological functions of small molecules. Indeed, around 20% of leading drugs contain at least one fluorine atom. Yet, despite profound effects of fluorination on conformation, there is only a limited toolkit of reactions that enable stereoselective synthesis of fluorinated compounds. Aldolases are useful catalysts for the stereoselective synthesis of bioactive small molecules; however, despite fluoropyruvate being a viable nucleophile for some aldolases, the potential of aldolases to control the formation of fluorine-bearing stereocentres has largely been untapped...
January 20, 2017: Current Opinion in Chemical Biology
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