Laboratory of Chemistry of Metabolic Pathways
The Laboratory was established in 2017 on the basis of the Total Synthesis Group which was created in the Laboratory of Molecular technologies at IBCH RAS, headed by Sergey Lukyanov. The mission of the group is to apply organic synthesis to solving actual problems in biochemistry, molecular biology and medicinal chemistry.
- structural design and synthesis of model compounds for studying biochemical processes
- total synthesis of natural products
- design, synthesis and testing of drug candidates
- offering our expertise in organic synthesis to biological and biomedical researchers in collaborative projects
- Studies of fungal bioluminescence
Photograph by Professor Cassius Stevani (University of San Paulo, Brazil)
The Guardian about our work
- Studying bioluminescence of marine worms Chaetopterus variopedatus
Photograph courtesy Dimitri Deheyn, Scripps Institution of Oceanography at UC San Diego
- Studying Studying bioluminescence mechanism of Siberian earthworms Fridericia heliota
- Development of novel class of fluorescent dyes based on GFP chromophore
- Development of anti-influenza drug candidates based on structural analogs of Flutimide
- Enantioselective total synthesis of fungal terpenoid panal from bioluminescent fungus Panellus stipticus
- Studying luminescence mechanism of luminous fungi
- Studying biosynthetic origin of marine luciferins: coelenterazine and Cypridina luciferin
- Developing fluorogenic sensors to important protein targets
New analgesic drugs suitable for oral use have been developed
In collaboration with Laboratory of biomolecular modeling,  Laboratory of Biological Testing,  Laboratory of neuroreceptors and neuroregulators
Among acid-sensitive ion channels (ASIC) the ASIC1a and ASIC3 subunits are the most attractive pharmacological targets. The inhibition of these channels by specific ligands can treat many socially significant diseases, such as chronic and pathological pain, ischemic stroke, and Parkinson's disease. Sevanol, a natural lignan isolated from Thymus armeniacus, inhibits the activity of ASIC1a and ASIC3 isoforms and has a significant analgesic and anti-inflammatory effect. However its production by chemical synthesis is a labor and material consumption process from many stages. The structure-functional investigation allowed to minimize the structure of Sevanol and to keep both analgesic activity in animal models, and ASICs inhibitory effect for analogs. The location of Sevanols binding site in the Central vestibule of ASIC1a was predicted in mathematical modeling experiment and its competition with the FRRF-amide peptide for this binding site was proved by electrophysiology. Sevanols analogues had a significant analgesic and anti-inflammatory effect in animal models by various administration routes- intravenous or intramuscular (parenteral methods), as well as intranasal or oral (non-invasive methods). Cozy synthesis method developed for each analogs allow us to recommend these molecules as potential prodrugs, since the absence of side effects identified at this moment together with oral activity are potent competitive advantages of new molecules to existent analgesic drugs. The results were published in Pharmaceuticals (Basel) journal.
Created by: Osmanov D.I., Vladimirov A.A., Koshelev S.G., Andreev, Y.A., Kozlov S.A. from laboratory of neuroreceptors and neuroregulators, Belozerova, O.A., Kublitski V.S. from laboratory of metabolic pathways chemistry, Chugunov A.O., Efremov R.G. from laboratory of biomolecular modeling, Palikov V.A., Palikova, Y.A., Shaikhutdinova E.R., Dyachenko I.A. from laboratory of biological examination, and Gvozd A.N. from scientific center of biomedical technologies of the Federal medical-biological Agency.
- (2020). Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking. Pharmaceuticals (Basel) 13 (8), 1–21
Creation of plants with genetically encoded autoluminescence
In collaboration with Laboratory of molecular immunology,  Artificial Climate Station “BIOTRON”,  Group of synthetic biology,  Group of Plant Metabolic Engineering,  Group of molecular tags for optical nanoscopy,  Department of Biomolecular Chemistry
In Nature Biotechnology, scientists from IBCh RAS have announced the feasibility of creating plants that produce their own visible luminescence. It was revealed that bioluminescence found in some mushrooms is metabolically similar to the natural processes common among plants. By inserting DNA obtained from the mushroom Neonothopanus nambi, the scientists were able to create plants that glow much brighter than previously possible. Plants containing the mushroom DNA glow continuously throughout their lifecycle, from seedling to maturity. This biological light can be used for observing the inner workings of plants. In contrast to other commonly used forms of bioluminescence, such as from fireflies, unique chemical reagents are not necessary for sustaining mushroom bioluminescence.
- (2020). Plants with genetically encoded autoluminescence. Nat Biotechnol 38 (8), 944–946
Elucidation of molecular basis of Odontosyllis bioluminescence
In collaboration with Laboratory of biomolecular NMR-spectroscopy,  Laboratory of ligand-receptor interactions
The researchers from Yampolsky lab have successfully characterized three key low-molecular-weight components of Odontosyllis undecimdonta bioluminescence system: luciferin, oxyluciferin (Green) and a nonspecific luciferin oxidation product (Pink). These compounds were revealed to be highly unusual tricyclic heterocycles containing three sulfur atoms in different electronic states. Together the structures of these low-molecular-weight components of Odontosyllis bioluminescent system have enabled us to propose chemical transformation pathways for the enzymatic (luminescent) and non-enzymatic (dark) oxidation of luciferin. Moreover Odontosyllis oxyluciferin was established to be the only green primary emitter described for any known bioluminescent marine organism.
- (2019). Bioluminescence chemistry of fireworm Odontosyllis. Proc Natl Acad Sci U S A 116 (38), 18911–18916
Scientists uncovered a mechanism of fungal luminescence and created luminescent yeasts
In collaboration with Group of synthetic biology
Scientists from the Institute of Bioorganic Chemistry in Moscow and Krasnoyarsk Federal Research Center together with their Russian and foreign colleagues have fully described the mechanism of fungal luminescence. They found that fungi utilize only four key enzymes to produce light and that transfer of these enzymes into any other organisms makes them bioluminescent. To illustrate this, the authors have created a luminescent yeast strain visible to the naked eye. The theoretical and experimental parts of the study were supported by Russian Science Foundation. The results of the study are published in the journal Proceedings of the National Academy of Sciences.
Decoding of the mechanism of fungal luminescence become possible because of preceding research in this field. Back in the early 19th century, it was discovered that it was mycelium that made rotten trees glow. In 2009, Anderson G. Oliveira and Cassius V. Stevani, co-authors of the present paper, determined that a single biochemical mechanism is shared by all fungi emitting light. In 2015–2017, a team of Russian scientists led by Ilia Yampolsky made a series of key discoveries. In particular, the team determined the structure of luciferin, the molecule that emits light when oxidized.
- (2018). Genetically encodable bioluminescent system from fungi. Proc Natl Acad Sci U S A 115 (50), 12728–12732
A method of protein labeling in live cells based on fluorogen and fluorogen-binding protein
In collaboration with Group of synthetic biology,  Group of chemistry of heterocyclic compounds,  Laboratory of genetically encoded molecular tools
We developed a new method of target protein labeling called Protein-PAINT. This method is based on reversible binding of a protein domain with a fluorogenic dye that leads to a strong increase in fluorescence intensity. Using computer molecular docking we engineered three mutants of bacterial lipocalin Blc with different affinities to the fluorogen. It was shown that the fluorogen enters live cell quickly and stains target proteins fused with the Blc mutants. The new method ensures an order of magnitude higher photostability of the fluorescence signal in comparison with fluorescent proteins. Protein-PAINT also enables prolonged super-resolution fluorescence microscopy of living cells in both single molecule detection and stimulated emission depletion regimes.
- (2017). Protein labeling for live cell fluorescence microscopy with a highly photostable renewable signal. Chem Sci 8 (10), 7138–7142
Mechanism of Fungal Bioluminescence study
The structure of fungal oxyluciferin was determined for the first time. A unique mechanism of bioluminescence, consisting of carbon dioxide cleavage through retro-[4 + 2]cycloaddition was proposed. Conclusions are supported by theoretical and experimental analysis, including the synthesis of the [18O]-labeled endoperoxide of the native luciferin. A number of artificial fungal luciferins with varying bioluminescence spectra were obtained.
- (2017). Mechanism and color modulation of fungal bioluminescence. Sci Adv 3 (4), e1602847
- (2016). A Tale of Two Luciferins: Fungal and Earthworm New Bioluminescent Systems. Acc Chem Res 49 (11), 2372–2380
- (2016). 1001 lights: Luciferins, luciferases, their mechanisms of action and applications in chemical analysis, biology and medicine. Chem Soc Rev 45 (21), 6048–6077
Synthesis of the core structure of fungal terpenoid Panal - a component of bioluminescent fungus Panellus stipticus
The structure of panal, an earlier presumed fungal luciferin precursor, was determined in 1988 by Nakamura and colleagues [Nakamura H, Kishi Y, Shimomura O. Tetrahedron 1988, 44, 1597]. Panal is a cadalane-type bicyclic sesquiterpenoid, total synthesis of which was carried out using the Diels-Alder cycloaddition, followed by Barbier and metathesis reactions.
- (2017). Synthesis of Panal Terpenoid Core. Synlett 28 (5), 583–588
The structure of a key bioluminescent substrate of higher fungi was elucidated
For the first time the structure of fungal luciferin was identified. Also the mechanism of it's biosynthesis via hydroxylation of secondary fungal metabolite hispidin by NADPH-dependent enzyme was determined. Luciferin (3-hydroxyhispidin) is a substrate of the enzyme luciferase in a bioluminescence reaction. The structures of the luciferin and it's precursor were proven by methods of NMR spectroscopy and mass spectrometry. It is shown that the luciferin is a common bioluminescent substrate for a number of higher fungi.
- (2015). The Chemical Basis of Fungal Bioluminescence. Angew Chem Int Ed Engl 54 (28), 8124–8128
The mechanism of bioluminescence of siberian worm Fridericia heliota was studied
Structure of Fridericia oxyluciferin was elucidated: oxyluciferin is a product of oxidative decarboxylation of luciferin from Fridericia heliota in the presence of luciferase. The mechanism of Fridericia bioluminescencewas studied: it includes the step of activating the carboxyl group of lysine via formation of an adenylate intermediate, cyclization to oxetanone and it's decay to the excited oxyluciferin molecule.
- (2015). Novel Mechanism of Bioluminescence: Oxidative Decarboxylation of a Moiety Adjacent to the Light Emitter of Fridericia Luciferin. Angew Chem Int Ed Engl 54 (24), 7065–7067
- (2015). Novel peptide chemistry in terrestrial animals: Natural luciferin analogues from the bioluminescent earthworm fridericia heliota. Chemistry 21 (10), 3942–3947