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Publications - Bioorganic Chemistry

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Publications

Camargo, F. D. G.; Santamaria-Torres, M.; Cala, M. P.; Guevara-Suarez, M.; Restrepo, S.; Sánchez-Camargo, A.; Fernández-Niño, M.; Corujo, M.; Gallo Molina, A. C.; Cifuentes, J.; Serna, J. A.; Cruz, J. C.; Muñoz-Camargo, C.; Barrios, A. F. G.; Genome-scale metabolic reconstruction, non-targeted LC-QTOF-MS based metabolomics data, and evaluation of anticancer activity of Cannabis sativa leaf extracts Metabolites 13, 788, (2023) DOI: 10.3390/metabo13070788

Over the past decades, Colombia has suffered complex social problems related to illicit crops, including forced displacement, violence, and environmental damage, among other consequences for vulnerable populations. Considerable effort has been made in the regulation of illicit crops, predominantly Cannabis sativa, leading to advances such as the legalization of medical cannabis and its derivatives, the improvement of crops, and leaving an open window to the development of scientific knowledge to explore alternative uses. It is estimated that C. sativa can produce approximately 750 specialized secondary metabolites. Some of the most relevant due to their anticancer properties, besides cannabinoids, are monoterpenes, sesquiterpenoids, triterpenoids, essential oils, flavonoids, and phenolic compounds. However, despite the increase in scientific research on the subject, it is necessary to study the primary and secondary metabolism of the plant and to identify key pathways that explore its great metabolic potential. For this purpose, a genome-scale metabolic reconstruction of C. sativa is described and contextualized using LC-QTOF-MS metabolic data obtained from the leaf extract from plants grown in the region of Pesca-Boyaca, Colombia under greenhouse conditions at the Clever Leaves facility. A compartmentalized model with 2101 reactions and 1314 metabolites highlights pathways associated with fatty acid biosynthesis, steroids, and amino acids, along with the metabolism of purine, pyrimidine, glucose, starch, and sucrose. Key metabolites were identified through metabolomic data, such as neurine, cannabisativine, cannflavin A, palmitoleic acid, cannabinoids, geranylhydroquinone, and steroids. They were analyzed and integrated into the reconstruction, and their potential applications are discussed. Cytotoxicity assays revealed high anticancer activity against gastric adenocarcinoma (AGS), melanoma cells (A375), and lung carcinoma cells (A549), combined with negligible impact against healthy human skin cells.
Preprints

Illig, A.-M.; Siedhoff, N. E.; Schwaneberg, U.; Davari, M. D.; A hybrid model combining evolutionary probability and machine learning leverages data-driven protein engineering bioRxiv (2022) DOI: 10.1101/2022.06.07.495081

Protein engineering through directed evolution and (semi-)rational approaches has been applied successfully to optimize protein properties for broad applications in molecular biology, biotechnology, and biomedicine. The potential of protein engineering is not yet fully realized due to the limited screening throughput hampering the efficient exploration of the vast protein sequence space. Data-driven strategies have emerged as a powerful tool to leverage protein engineering by providing a model of the sequence-fitness landscape that can exhaustively be explored in silico and capitalize on the high diversity potential offered by nature However, as both the quality and quantity of the inputted data determine the success of such approaches, the applicability of data-driven strategies is often limited due to sparse data. Here, we present a hybrid model that combines direct coupling analysis and machine learning techniques to enable data-driven protein engineering when only few labeled sequences are available. Our method achieves high performance in predicting a protein’s fitness based on its sequence regardless of the number of sequences-fitness pairs in the training dataset. Besides reducing the computational effort compared to state-of-the-art methods, it outperforms them for sparse data situations, i.e., 50 − 250 labeled sequences available for training. In essence, the developed method is auspicious for data-driven protein engineering, especially for protein engineers who have only access to a limited amount of data for sequence-fitness landscape modeling.
Publications

Vasco, A. V.; Ceballos, L. G.; Wessjohann, L. A.; Rivera, D. G.; Multicomponent functionalization of the octreotide peptide macrocyclic scaffold Eur. J. Org. Chem. 2022, e202200687, (2022) DOI: 10.1002/ejoc.202200687

The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an onresin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.
Publications

Tousif, M. I.; Nazir, M.; Saleem, M.; Tauseef, S.; Shafiq, N.; Hassan, L.; Hussain, H.; Montesano, D.; Naviglio, D.; Zengin, G.; Ahmad, I.; Psidium guajava L. an incalculable but underexplored food crop: Its phytochemistry, ethnopharmacology, and industrial applications Molecules 27, 7016, (2022) DOI: 10.3390/molecules27207016

Psidium guajava L. (guava) is a small tree known for its fruit flavor that is cultivated almost around the globe in tropical areas. Its fruit is amazingly rich in antioxidants, vitamin C, potassium, and dietary fiber. In different parts of the world, this plant holds a special place with respect to fruit and nutritional items. Pharmacological research has shown that this plant has more potential than just a fruit source; it also has beneficial effects against a variety of chronic diseases due to its rich nutritional and phytochemical profile. The primary goal of this document is to provide an updated overview of Psidium guajava L. and its bioactive secondary metabolites, as well as their availability for further study, with a focus on the health benefits and potential industrial applications. There have been several studies conducted on Psidium guajava L. in relation to its use in the pharmaceutical industry. However, its clinical efficacy and applications are still debatable. Therefore, in this review a detailed study with respect to phytochemistry of the plant through modern instruments such as GC and LC-MS has been discussed. The biological activities of secondary metabolites isolated from this plant have been extensively discussed. In order to perform long-term clinical trials to learn more about their effectiveness as drugs and applications for various health benefits, a structure activity relationship has been established. Based on the literature, it is concluded that this plant has a wide variety of biopharmaceutical applications. As a whole, this article calls for long-term clinical trials to obtain a greater understanding of how it can be used to treat different diseases.
Publications

Sun, X.; Chen, L.; Yan, H.; Cui, L.; Hussain, H.; Xie, L.; Liu, J.; Jiang, Y.; Meng, Z.; Cao, G.; Park, J.; Wang, D.; An efficient high‐speed counter‐current chromatography method for the preparative separation of potential antioxidant from Paeonia lactiflora Pall. combination of in vitro evaluation and molecular docking J Sep Sci 45, 1856-1865, (2022) DOI: 10.1002/jssc.202200082

Paeonia lactiflora Pall., one of the most famous classical herbal medicine, has been used to treat diseases for over 1200 years. In this research, the functional ingredients were purified by online-switch two-dimensional high-speed counter-current chromatography combined with inner-recycling and continuous injection mode. The antioxidant activity was evaluated by investigating the 2,2’-azobis (2-amidinopropane) dihydrochloride-induced oxidant damage in vitro and confirmed through molecular docking. n-Butanol/ethyl acetate/water (2:3:5, v/v) solvent system was used for the first dimensional separation and optimized the sample loading. Two pure compounds and a polyphenol-enriched fraction were separated. The polyphenol-enriched fraction was separated with a solvent system n-hexane/ethyl acetate/methanol/water (2:8:4:6, v/v) with continuous injection mode. Five compounds were successfully separated, including gallic acid (1), methyl gallate (2), albiflorin (3), paeoniflorin (4), and ethyl gallate (5). Their structures were identified by mass spectrometry and nuclear magnetic resonance. The results from antioxidant effect showed that albiflorin had stronger antioxidant activity. Molecular docking results indicated that the affinity energy of the identified compounds ranged from -3.79 to -8.22 kcal/mol and albiflorin showed the lowest affinity energy. Overall, all those findings suggested that the strong antioxidant capacity of albiflorin can be potentially used for treatment of diseases that caused by oxidation.
Publications

Soboleva, A.; Frolova, N.; Bureiko, K.; Shumilina, J.; Balcke, G. U.; Zhukov, V. A.; Tikhonovich, I. A.; Frolov, A.; Dynamics of Reactive Carbonyl Species in Pea Root Nodules in Response to Polyethylene Glycol (PEG)-Induced Osmotic Stress Int. J. Mol. Sci. 23, 2726, (2022) DOI: 10.3390/ijms23052726

Drought dramatically affects crop productivity worldwide. For legumes this effect is especially pronounced, as their symbiotic association with rhizobia is highly-sensitive to dehydration. This might be attributed to the oxidative stress, which ultimately accompanies plants’ response to water deficit. Indeed, enhanced formation of reactive oxygen species in root nodules might result in up-regulation of lipid peroxidation and overproduction of reactive carbonyl compounds (RCCs), which readily modify biomolecules and disrupt cell functions. Thus, the knowledge of the nodule carbonyl metabolome dynamics is critically important for understanding the drought-related losses of nitrogen fixation efficiency and plant productivity. Therefore, here we provide, to the best of our knowledge, for the first time a comprehensive overview of the pea root nodule carbonyl metabolome and address its alterations in response to polyethylene glycol-induced osmotic stress as the first step to examine the changes of RCC patterns in drought treated plants. RCCs were extracted from the nodules and derivatized with 7-(diethylamino)coumarin-3-carbohydrazide (CHH). The relative quantification of CHH-derivatives by liquid chromatography-high resolution mass spectrometry with a post-run correction for derivative stability revealed in total 194 features with intensities above 1 × 105 counts, 19 of which were down- and three were upregulated. The upregulation of glyceraldehyde could accompany non-enzymatic conversion of glyceraldehyde-3-phosphate to methylglyoxal. The accumulation of 4,5-dioxovaleric acid could be the reason for down-regulation of porphyrin metabolism, suppression of leghemoglobin synthesis, inhibition of nitrogenase and degradation of legume-rhizobial symbiosis in response to polyethylene glycol (PEG)-induced osmotic stress effect. This effect needs to be confirmed with soil-based drought models.
Publications

Smolikova, G.; Strygina, K.; Krylova, E.; Vikhorev, A.; Bilova, T.; Frolov, A.; Khlestkina, E.; Medvedev, S.; Seed-to-seedling transition in Pisum sativum L.: A transcriptomic approach Plants 11, 1686, (2022) DOI: 10.3390/plants11131686

The seed-to-seedling transition is a crucial step in the plant life cycle. The transition occurs at the end of seed germination and corresponds to the initiation of embryonic root growth. To improve our understanding of how a seed transforms into a seedling, we germinated the Pisum sativum L. seeds for 72 h and divided them into samples before and after radicle protrusion. Before radicle protrusion, seeds survived after drying and formed normally developed seedlings upon rehydration. Radicle protrusion increased the moisture content level in seed axes, and the accumulation of ROS first generated in the embryonic root and plumule. The water and oxidative status shift correlated with the desiccation tolerance loss. Then, we compared RNA sequencing-based transcriptomics in the embryonic axes isolated from pea seeds before and after radicle protrusion. We identified 24,184 differentially expressed genes during the transition to the post-germination stage. Among them, 2101 genes showed more prominent expression. They were related to primary and secondary metabolism, photosynthesis, biosynthesis of cell wall components, redox status, and responses to biotic stress. On the other hand, 415 genes showed significantly decreased expression, including the groups related to water deprivation (eight genes) and response to the ABA stimulus (fifteen genes). We assume that the water deprivation group, especially three genes also belonging to ABA stimulus (LTI65, LTP4, and HVA22E), may be crucial for the desiccation tolerance loss during a metabolic switch from seed to seedling. The latter is also accompanied by the suppression of ABA-related transcription factors ABI3, ABI4, and ABI5. Among them, HVA22E, ABI4, and ABI5 were highly conservative in functional domains and showed homologous sequences in different drought-tolerant species. These findings elaborate on the critical biochemical pathways and genes regulating seed-to-seedling transition.
Publications

Shah, M. A.; Uddin, A.; Shah, M. R.; Ali, I.; Ullah, R.; Hannan, P. A.; Hussain, H.; Synthesis and characterization of novel hydrazone derivatives of isonicotinic hydrazide and their evaluation for antibacterial and cytotoxic potential Molecules 27, 6770, (2022) DOI: 10.3390/molecules27196770

Hydrazones are active compounds having an azomethine –NHN=CH group and are widely studied owing to their ease of preparation and diverse pharmacological benefits. Novel isonicotinic hydrazone derivatives of vanillin aldehyde and salicyl aldehyde were synthesized that had azomethine linkages and were characterized by UV–Visible, FTIR, EI-MS, 1H-NMR and 13C-NMR spectroscopy. The compounds were screened for their antibacterial activity against Staphylococcus aureus, Bacillus subtilus, and Escherichia coli using disc diffusion and minimum inhibitory concentration (MIC) methods. For cytotoxicity, a brine shrimp lethality test was performed to calculate the lethal concentration (LC50). The results demonstrated appreciable antibacterial activities against the applied strains, amongst which the compounds coded NH3 and NH5 showed maximum inhibition and MIC responses. In terms of cytotoxic activity, the maximum effect was observed in compound NH5 and NH6 treatments with minimum survival percentages of 36.10 ± 3.45 and 32.44 ± 2.0, respectively. These hydrazones could be potential candidates in antitumorigenic therapy against various human cancer cells.
Publications

Rajakumara, E.; Abhishek, S.; Nitin, K.; Saniya, D.; Bajaj, P.; Schwaneberg, U.; Davari, M. D.; Structure and cooperativity in substrate–enzyme interactions: Perspectives on enzyme engineering and inhibitor design ACS Chem. Biol. 17, 266-280, (2022) DOI: 10.1021/acschembio.1c00500

Enzyme-based synthetic chemistry provides a green way to synthesize industrially important chemical scaffolds and provides incomparable substrate specificity and unmatched stereo-, regio-, and chemoselective product formation. However, using biocatalysts at an industrial scale has its challenges, like their narrow substrate scope, limited stability in large-scale one-pot reactions, and low expression levels. These limitations can be overcome by engineering and fine-tuning these biocatalysts using advanced protein engineering methods. A detailed understanding of the enzyme structure and catalytic mechanism and its structure–function relationship, cooperativity in binding of substrates, and dynamics of substrate–enzyme–cofactor complexes is essential for rational enzyme engineering for a specific purpose. This Review covers all these aspects along with an in-depth categorization of various industrially and pharmaceutically crucial bisubstrate enzymes based on their reaction mechanisms and their active site and substrate/cofactor-binding site structures. As the bisubstrate enzymes constitute around 60% of the known industrially important enzymes, studying their mechanism of actions and structure–activity relationship gives significant insight into deciding the targets for protein engineering for developing industrial biocatalysts. Thus, this Review is focused on providing a comprehensive knowledge of the bisubstrate enzymes’ structure, their mechanisms, and protein engineering approaches to develop them into industrial biocatalysts.
Publications

Quimque, M. T. J.; Magsipoc, R. J. Y.; Llames, L. C. J.; Flores, A. I. G.; Garcia, K. Y. M.; Ratzenböck, A.; Hussain, H.; Macabeo, A. P. G.; Polyoxygenated cyclohexenes from Uvaria grandiflora with multi-enzyme targeting properties relevant in Type 2 Diabetes and Obesity ACS Omega 7, 36856-36864, (2022) DOI: 10.1021/acsomega.2c05544

Shikimic acid-derived polyoxygenated cyclohexene natural products commonly occurring in several species of the Uvaria represent natural products with promising biological activities. While a number of derivatives have been reported from Uvaria grandiflora (U. grandiflora), further studies are needed to discover additional bioactive congeners, particularly derivatives with multi-protein tarUvaria grandiflora (U. grandiflora)Uvaria grandiflora (U. grandiflora)d in diseases such as diabetes and obesity. In this paper, isolation and identification of a new highly oxygenated cyclohexene, uvagrandol (1), along with the known compound (-)-zeylenone (2) from the DCM sub-extract of U. grandiflora following in vitro and in silico assessment of their enzyme inhibitory properties against α-glucosidase, dipeptidyl peptidase IV, porcine lipase, and human recombinant monoacylglycerol lipase are reported. The structure of 1 was elucidated using 1D and 2D NMR data analysis. The absolute configuration of 1 was established by quantum chemical calculations via the Gauge-Independent Atomic Orbital (GIAO) NMR method followed by TDDFT-Electronic Circular Dichroism (ECD) calculations. The structures of the eight possible stereoisomers were optimized by means of DFT calculations (B3LYP/6-31+G[d,p] in vacuum), and then their isotropic shielding tensors were obtained using the GIAO method at mPW1PW91/6-31G(d,p) in chloroform. Through DP4+, the isomer of configuration (1S,2S,3R,6R) for 1 was predicted with 96.3% probability. Compounds 1 and 2 significantly inhibited the four target enzymes in vitro. Binding studies through molecular docking simulations showed strong binding affinities for (-)-zeylenone (2), thus validating the in vitro results. Our findings suggest the potential of polyoxygenated cyclohexenes, in particular (-)-zeylenone (2), in anti-diabetic and anti-obesity drug discovery.
  • Die Leibniz-Gemeinschaft
  • Digitalization in agriculture
  • Universität Halle
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