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Science (New York, N.Y.) Nov 2017Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We...
Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.
Topics: Amination; Ammonia; Animals; Aspartic Acid; Biocatalysis; Breast Neoplasms; Cell Proliferation; Female; Glutamate Dehydrogenase; Humans; MCF-7 Cells; Mice; Proline; RNA, Small Interfering; Tumor Microenvironment
PubMed: 29025995
DOI: 10.1126/science.aam9305 -
Current Opinion in Chemical Biology Apr 2017Imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines. The development of bioinformatics... (Review)
Review
Imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines. The development of bioinformatics tools and searchable databases has led to the identification of a diverse range of new IRED biocatalysts that have been characterised and employed in different synthetic processes. This review describes the latest developments in the structural and mechanistic aspects of IREDs, together with synthetic applications of these enzymes, and identifies ongoing and future challenges in the field.
Topics: Amination; Biocatalysis; Imines; Oxidation-Reduction; Oxidoreductases
PubMed: 28038349
DOI: 10.1016/j.cbpa.2016.11.022 -
Current Opinion in Chemical Biology Apr 2018Amine transaminases are important biocatalysts for the synthesis of chiral primary amines. Unlike many enzymes that have been employed for the synthesis of optically... (Review)
Review
Amine transaminases are important biocatalysts for the synthesis of chiral primary amines. Unlike many enzymes that have been employed for the synthesis of optically active amines, amine transaminases are capable of asymmetric synthesis and do not rely on costly cofactors that must be regenerated in situ. However, their application as general catalysts for the preparation of amines is hampered by a limited substrate scope, substrate and (co)product inhibition and difficulties associated with displacing challenging reaction equilibrium. There has been important progress made to overcome these challenges, including the development of enzymes with broader substrate scope and the design of methodology to effectively displace the reaction equilibrium. Amine transaminases are also being applied in an increasing range of (chemo)enzymatic cascades and immobilized for applications in flow.
Topics: Amines; Biocatalysis; Biotransformation; Stereoisomerism; Substrate Specificity; Transaminases
PubMed: 29278779
DOI: 10.1016/j.cbpa.2017.12.007 -
Current Opinion in Chemical Biology Apr 2018Chiral amines feature in a large number of small molecule pharmaceuticals, and thus methods for their asymmetric synthesis are of considerable interest. Biocatalytic... (Review)
Review
Chiral amines feature in a large number of small molecule pharmaceuticals, and thus methods for their asymmetric synthesis are of considerable interest. Biocatalytic approaches have come to the fore in recent years as these offer advantages of superior atom economy, mild reaction conditions and excellent stereoselectivity. Advances in redox cofactor process technology have meant that oxidoreductase enzymes in particular now have growing potential as industrial catalysts for amine formation. In this review we survey recent developments in the discovery and application of oxidoreductase enzymes for amine production, including Monoamine Oxidases (MAOs), engineered and natural Amine Dehydrogenases (AmDHs), Imine Reductases (IREDs) and Reductive Aminases (RedAms), in addition to their application in enzyme cascades.
Topics: Amination; Amines; Biocatalysis; Coenzymes; Enzymes; Oxidation-Reduction; Protein Engineering; Small Molecule Libraries; Stereoisomerism
PubMed: 29100099
DOI: 10.1016/j.cbpa.2017.09.008 -
Journal of the American Chemical Society Apr 2018We describe the development of an arenophile-mediated, nickel-catalyzed dearomative trans-1,2-carboamination protocol. A range of readily available aromatic compounds...
We describe the development of an arenophile-mediated, nickel-catalyzed dearomative trans-1,2-carboamination protocol. A range of readily available aromatic compounds was converted to the corresponding dienes using Grignard reagents as nucleophiles. This strategy provided products with exclusive trans-selectivity and high enantioselectivity was observed in case of benzene and naphthalene. The utility of this methodology was showcased by controlled and stereoselective preparation of small, functionalized molecules.
Topics: Amination; Catalysis; Molecular Structure; Nickel; Stereoisomerism
PubMed: 29544244
DOI: 10.1021/jacs.8b01726 -
Journal of the American Chemical Society Jun 2022We report a total synthesis of the alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces...
We report a total synthesis of the alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol's complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent -1,3-bis(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.
Topics: Alkaloids; Alkenes; Amination; Heterocyclic Compounds, 4 or More Rings; Stereoisomerism
PubMed: 35699935
DOI: 10.1021/jacs.2c04487 -
Molecules (Basel, Switzerland) Jun 2022In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal,... (Review)
Review
In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal, catalyzed, or noncatalyzed reaction conditions. The aforementioned reactions in the aim to prepare basic five-, six-, organometallic heterocyclic-membered systems and/or their fused analogs. This review article also provides a report on the developed methods describing the synthesis of various heterocycles from organic azides, especially those reported in recent papers (till 2020). At the outset, this review groups the synthetic methods of organic azides into different categories. Secondly, the review deals with the functionality of the azido group in chemical reactions. This is followed by a major section on the following: (1) the synthetic tools of various heterocycles from the corresponding organic azides by one-pot domino reaction; (2) the utility of the chosen catalysts in the chemoselectivity favoring C-H and C-N bonds; (3) one-pot procedures (i.e., Ugi four-component reaction); (4) nucleophilic addition, such as Aza-Michael addition; (5) cycloaddition reactions, such as [3+2] cycloaddition; (6) mixed addition/cyclization/oxygen; and (7) insertion reaction of C-H amination. The review also includes the synthetic procedures of fused heterocycles, such as quinazoline derivatives and organometal heterocycles (i.e., phosphorus-, boron- and aluminum-containing heterocycles). Due to many references that have dealt with the reactions of azides in heterocyclic synthesis (currently more than 32,000), we selected according to generality and timeliness. This is considered a recent review that focuses on selected interesting examples of various heterocycles from the mechanistic aspects of organic azides.
Topics: Amination; Azides; Catalysis; Cyclization; Cycloaddition Reaction
PubMed: 35744839
DOI: 10.3390/molecules27123716 -
Journal of the American Chemical Society Jun 2023Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts,...
Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20-75 °C, pH 5-7.5). Specifically, Fe or Al, the two most abundant metals in the Earth's crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe alone, whereas Al-PL was 85-fold faster than PL alone and 38-fold faster than Al alone. Under milder conditions, reactions catalyzed by Al-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the p of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.
Topics: Pyridoxal; Pyridoxal Phosphate; Metals; Coenzymes; Amination; Catalysis
PubMed: 37278531
DOI: 10.1021/jacs.3c03542 -
Journal of the American Chemical Society Nov 2023Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with...
Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with an IC of 25 nM against PANC-1, making it a potential candidate for therapeutic development. We report a synthetic approach to aleutianamine wherein the unique [3.3.1] ring system and tertiary sulfide of this alkaloid were constructed via a novel palladium-catalyzed dearomative thiophene functionalization. Other highlights of the synthesis include a palladium-catalyzed decarboxylative pinacol-type rearrangement of an allylic carbonate to install a ketone and a late-stage oxidative amination. This concise and convergent strategy will enable access to analogues of aleutianamine and further investigation of the biological activity of this unique natural product.
Topics: Humans; Palladium; Catalysis; Stereoisomerism; Amination; Biological Products
PubMed: 37967164
DOI: 10.1021/jacs.3c10212 -
Chemical Communications (Cambridge,... Nov 2022Amine-containing natural products are an important class of therapeutic compounds. Herein, we report a chemoselective approach to catch and enrich amine-containing...
Amine-containing natural products are an important class of therapeutic compounds. Herein, we report a chemoselective approach to catch and enrich amine-containing natural products, and release them as underivatized compounds. The strategy exploits the selectivity of the enzyme legumain for the specific release of amine-containing natural products.
Topics: Amines; Biological Products
PubMed: 36264220
DOI: 10.1039/d2cc04905h