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Natural Product Reports Sep 2018A new review covering up to 2018 Sphingolipids are essential molecules that, despite their long history, are still stimulating interest today. The reasons for this are... (Review)
Review
A new review covering up to 2018 Sphingolipids are essential molecules that, despite their long history, are still stimulating interest today. The reasons for this are that, as well as playing structural roles within cell membranes, they have also been shown to perform a myriad of cell signalling functions vital to the correct function of eukaryotic and prokaryotic organisms. Indeed, sphingolipid disregulation that alters the tightly-controlled balance of these key lipids has been closely linked to a number of diseases such as diabetes, asthma and various neuropathologies. Sphingolipid biogenesis, metabolism and regulation is mediated by a large number of enzymes, proteins and second messengers. There appears to be a core pathway common to all sphingolipid-producing organisms but recent studies have begun to dissect out important, species-specific differences. Many of these have only recently been discovered and in most cases the molecular and biochemical details are only beginning to emerge. Where there is a direct link from classic biochemistry to clinical symptoms, a number a drug companies have undertaken a medicinal chemistry campaign to try to deliver a therapeutic intervention to alleviate a number of diseases. Where appropriate, we highlight targets where natural products have been exploited as useful tools. Taking all these aspects into account this review covers the structural, mechanistic and regulatory features of sphingolipid biosynthetic and metabolic enzymes.
Topics: Alcohol Oxidoreductases; Aldehyde-Lyases; Animals; Fungal Proteins; Humans; Mutation; Phosphotransferases (Alcohol Group Acceptor); Serine C-Palmitoyltransferase; Sphingolipids
PubMed: 29863195
DOI: 10.1039/c8np00019k -
Applied Microbiology and Biotechnology Dec 20182-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective... (Review)
Review
2-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective C-C bond formation between acetaldehyde and numerous other aldehydes. However, the practical application of DERA as a biocatalyst is limited by its poor tolerance towards industrially relevant concentrations of aldehydes, in particular acetaldehyde. Therefore, the development of proper experimental conditions, including protein engineering and/or immobilization on appropriate supports, is required. The present review is aimed to provide a brief overview of DERA, its history, and progress made in understanding the functioning of the enzyme. Furthermore, the current understanding regarding aldehyde resistance of DERA and the various optimizations carried out to modify this property are discussed.
Topics: Acetaldehyde; Aldehyde-Lyases; Aldehydes; Catalysis; Protein Conformation; Protein Engineering; Ribosemonophosphates; Substrate Specificity
PubMed: 30284013
DOI: 10.1007/s00253-018-9392-8 -
Critical Reviews in Biochemistry and... 2015Sphingolipids represent an important class of bioactive signaling lipids which have key roles in numerous cellular processes. Over the last few decades, the levels of... (Review)
Review
Sphingolipids represent an important class of bioactive signaling lipids which have key roles in numerous cellular processes. Over the last few decades, the levels of bioactive sphingolipids and/or their metabolizing enzymes have been realized to be important factors involved in disease development and progression, most notably in cancer. Targeting sphingolipid-metabolizing enzymes in disease states has been the focus of many studies and has resulted in a number of pharmacological inhibitors, with some making it into the clinic as therapeutics. In order to better understand the regulation of sphingolipid-metabolizing enzymes as well as to develop much more potent and specific inhibitors, the field of sphingolipids has recently taken a turn toward structural biology. The last decade has seen the structural determination of a number of sphingolipid enzymes and effector proteins. In these terms, one of the most complete arms of the sphingolipid pathway is the sphingosine-1-phosphate (S1P) arm. The structures of proteins involved in the function and regulation of S1P are being used to investigate further the regulation of said proteins as well as in the design and development of inhibitors as potential therapeutics.
Topics: Aldehyde-Lyases; Animals; Binding Sites; Biological Transport; Enzyme Inhibitors; Humans; Ligands; Lysophospholipids; Membrane Transport Modulators; Models, Molecular; Molecular Conformation; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Second Messenger Systems; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 25923252
DOI: 10.3109/10409238.2015.1039115 -
Current Opinion in Chemical Biology Apr 2014Aldolases are seen as an attractive route to the production of biologically important compounds due to their ability to form carbon-carbon bonds. However, for many... (Review)
Review
Aldolases are seen as an attractive route to the production of biologically important compounds due to their ability to form carbon-carbon bonds. However, for many industrial reactions there are no naturally occurring enzymes, and so many different engineering approaches have been used to address this problem. Engineering methods have been used to alter the stability, substrate specificity and stereospecificity of aldolases to produce excellent enzymes for biocatalytic processes. Recently greater understanding of the aldolase mechanism has allowed many successes with both rational engineering approaches and computational design of aldolases. Rational engineering approaches have produced desired enzymes quickly and efficiently while combination of computational design with laboratory methods has created enzymes with activity approaching that of natural enzymes.
Topics: Aldehyde-Lyases; Biocatalysis; Catalytic Domain; Enzyme Stability; Humans; Protein Engineering; Substrate Specificity
PubMed: 24780276
DOI: 10.1016/j.cbpa.2013.12.010 -
Angewandte Chemie (International Ed. in... Apr 2021Multienzyme cascade biocatalysis is an efficient synthetic process, avoiding the isolation/purification of intermediates and shifting the reaction equilibrium to the...
Multienzyme cascade biocatalysis is an efficient synthetic process, avoiding the isolation/purification of intermediates and shifting the reaction equilibrium to the product side.. However, multienzyme systems are often limited by their incompatibility and cross-reactivity. Herein, we report a multi-responsive emulsion to proceed multienzyme reactions sequentially for high reactivity. The emulsion is achieved using a CO , pH, and thermo-responsive block copolymer as a stabilizer, allowing the on-demand control of emulsion morphology and phase composition. Applying this system to a three-step cascade reaction enables the individual optimal condition for each enzyme, and a high overall conversion (ca. 97 % of the calculated limit) is thereby obtained. Moreover, the multi-responsiveness of the emulsion allows the facile and separate yielding/recycling of products, polymers and active enzymes. Besides, the system could be scaled up with a good yield.
Topics: Alcohol Dehydrogenase; Aldehyde-Lyases; Biocatalysis; Emulsions; Fungal Proteins; Lipase; Polymers
PubMed: 33480131
DOI: 10.1002/anie.202013737 -
Biochimica Et Biophysica Acta.... Jul 2020Long-chain fatty aldehydes are present in low concentrations in mammalian cells and serve as intermediates in the interconversion between fatty acids and fatty alcohols.... (Review)
Review
Long-chain fatty aldehydes are present in low concentrations in mammalian cells and serve as intermediates in the interconversion between fatty acids and fatty alcohols. The long-chain fatty aldehydes are generated by enzymatic hydrolysis of 1-alkyl-, and 1-alkenyl-glycerophospholipids by alkylglycerol monooxygenase, plasmalogenase or lysoplasmalogenase while hydrolysis of sphingosine-1-phosphate (S1P) by S1P lyase generates trans ∆2-hexadecenal (∆2-HDE). Additionally, 2-chloro-, and 2-bromo- fatty aldehydes are produced from plasmalogens or lysoplasmalogens by hypochlorous, and hypobromous acid generated by activated neutrophils and eosinophils, respectively while 2-iodofatty aldehydes are produced by excess iodine in thyroid glands. The 2-halofatty aldehydes and ∆2-HDE activated JNK signaling, BAX, cytoskeletal reorganization and apoptosis in mammalian cells. Further, 2-chloro- and 2-bromo-fatty aldehydes formed GSH and protein adducts while ∆2-HDE formed adducts with GSH, deoxyguanosine in DNA and proteins such as HDAC1 in vitro. ∆2-HDE also modulated HDAC activity and stimulated H3 and H4 histone acetylation in vitro with lung epithelial cell nuclear preparations. The α-halo fatty aldehydes elicited endothelial dysfunction, cellular toxicity and tissue damage. Taken together, these investigations suggest a new role for long-chain fatty aldehydes as signaling lipids, ability to form adducts with GSH, proteins such as HDACs and regulate cellular functions.
Topics: Aldehyde-Lyases; Aldehydes; Animals; Histone Deacetylases; Humans; Plasmalogens; Signal Transduction
PubMed: 32171908
DOI: 10.1016/j.bbalip.2020.158681 -
Mediators of Inflammation 2017Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis,... (Review)
Review
Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human , the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes.
Topics: Aldehyde-Lyases; Animals; Carcinogenesis; Cell Movement; Dendritic Cells; Humans; Inflammation; Inflammation Mediators; Lysophospholipids; Models, Biological; Mutation; Signal Transduction; Sphingosine; T-Lymphocytes
PubMed: 29333002
DOI: 10.1155/2017/7685142 -
Advances in Biological Regulation Jan 2012Sphingosine phosphate lyase (SPL) is an intracellular enzyme responsible for the irreversible catabolism of the lipid signaling molecule sphingosine-1-phosphate (S1P).... (Review)
Review
Sphingosine phosphate lyase (SPL) is an intracellular enzyme responsible for the irreversible catabolism of the lipid signaling molecule sphingosine-1-phosphate (S1P). SPL catalyzes the cleavage of S1P resulting in the formation of hexadecenal and ethanolamine phosphate. S1P functions as a ligand for a family of ubiquitously expressed G protein-coupled receptors that mediate autocrine and paracrine signals controlling cell migration, proliferation and programmed cell death pathways. S1P has also been implicated in developmental and pathological angiogenesis, cancer, inflammation, allergy, diabetes, lymphocyte trafficking and morphogenesis of the heart, kidney and brain as well as their response to ischemic injury. As the final enzyme in the sphingolipid degradative pathway, SPL commands the only exit point for sphingolipid intermediates and their flow into phospholipid metabolism. So, in addition to regulating S1P levels, SPL is the gatekeeper of a critical node of lipid metabolic flow. The recent crystallization of a prokaryotic SPL has provided insight into the function and potential regulation and drug targeting of this enzyme. Considering the many physiological and pathological functions of S1P signaling, it seems likely that targeting SPL to modulate S1P signaling could be useful in a variety of clinical contexts. In this review we discuss the recent highlights related to SPL-mediated biology, the structure of the SPL protein, the function of its products, new insights regarding the usefulness of SPL targeting in treating human diseases and the consequences of permanent SPL disruption in mice.
Topics: Aldehyde-Lyases; Animals; Humans; Models, Biological; Models, Theoretical; Phosphorylation; Sphingolipids
PubMed: 21946005
DOI: 10.1016/j.advenzreg.2011.09.015 -
Journal of Lipid Research Mar 2019Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs)... (Review)
Review
Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs) to yield a long-chain aldehyde and ethanolamine phosphate (EP). SPL guards the sole exit point of sphingolipid metabolism. Its inactivation causes product depletion and accumulation of upstream sphingolipid intermediates. The main substrate of the reaction, sphingosine-1-phosphate (S1P), is a bioactive lipid that controls immune-cell trafficking, angiogenesis, cell transformation, and other fundamental processes. The products of the SPL reaction contribute to phospholipid biosynthesis and programmed cell-death activation. The main features of SPL enzyme activity were first described in detail by Stoffel et al. in 1969. The first SPL-encoding gene was cloned from budding yeast in 1997. Reverse and forward genetic strategies led to the rapid identification of other genes in the pathway and their homologs in other species. Genetic manipulation of SPL-encoding genes in model organisms has revealed the contribution of sphingolipid metabolism to development, physiology, and host-pathogen interactions. In 2017, recessive mutations in the human SPL gene were identified as the cause of a novel inborn error of metabolism associated with nephrosis, endocrine defects, immunodeficiency, acanthosis, and neurological problems. We refer to this condition as SPL insufficiency syndrome (SPLIS). Here, we share our perspective on the 50-year history of SPL from discovery to disease, focusing on insights provided by model organisms regarding the pathophysiology of SPLIS and how SPLIS raises the possibility of a hidden role for sphingolipids in other disease conditions.
Topics: Aldehyde-Lyases; Animals; Disease; Humans; Phosphates
PubMed: 30635364
DOI: 10.1194/jlr.S091181 -
Trends in Pharmacological Sciences Jan 2011Sphingosine-1-phosphate (S1P) is a bioactive lipid with important functions in the immune system. S1P levels are regulated by the balance between its synthesis through... (Review)
Review
Sphingosine-1-phosphate (S1P) is a bioactive lipid with important functions in the immune system. S1P levels are regulated by the balance between its synthesis through sphingosine kinases and its degradation by S1P lyase. S1P signals through plasma membrane G-protein-coupled receptors (S1PR1-S1PR5) or acts directly on intracellular targets. Although it has long been known that the S1P-S1PR1 axis mediates T cell egress from lymphoid organs, recent studies have revealed intrinsic functions of S1P and its receptors in both innate and adaptive immune systems that are independent of immune cell trafficking. Here I summarize recent advances in understanding of the roles of S1P and S1P receptors in inflammatory and allergic responses and lymphocyte differentiation, which directly contribute to the regulation of inflammatory and autoimmune diseases. I also describe strategies to target S1P and S1P receptors for immune-mediated diseases, particularly the immunosuppressant FTY720 (fingolimod), which has recently become the first oral therapy for relapsing multiple sclerosis.
Topics: Aldehyde-Lyases; Animals; Cell Differentiation; Humans; Immunity, Innate; Inflammation; Lymphocytes; Lysophospholipids; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Signal Transduction; Sphingosine
PubMed: 21159389
DOI: 10.1016/j.tips.2010.11.002