The DOI matches its Crossref record; 75 of the 76 references it cites were found in a registry or an index.
A curated list of targeted optimized promiscuous ketoreductases (TOP-K)
Open accessPublished version of a preprint
Abstract
Enzymes are either specific or promiscuous catalysts in nature. The latter is portrayed by protein families like CYP450Es, Aldo-ketoreductases, and Short/Medium-chain dehydrogenases which participate in detoxification or secondary metabolite production. However, enzymes are evolutionarily ‘blind’ to an ever-increasing synthetic substrate library. Industries and labs have circumvented this by high-throughput screening or site-specific engineering to synthesize the product of interest. However, this paradigm entails cost and time-intensive one-enzyme, one-substrate catalysis model. One of the superfamilies regularly used for chiral alcohol synthesis are Short-chain dehydrogenases/reductases (SDRs). Our objective is to determine a superset of promiscuous SDRs that can catalyze multiple ketones. They are typically classified into shorter 'Classical' and longer 'Extended' type ketoreductases. However, current analysis of modelled SDRs reveals a length-independent conserved N-terminus Rossmann-fold and a variable substrate binding C-terminus substrate-binding region for both categories. The latter is recognized to influence the enzyme's flexibility and substrate promiscuity and we hypothesize these properties are directly linked with each other. We tested this by catalyzing ketone-intermediates with the essential and specific enzyme: FabG_E, as well as non-essential SDRs such as UcpA and IdnO. The experimental results confirmed this biochemical-biophysical association, making it an interesting filter for ascertaining promiscuous enzymes. Hence, we created a dataset of physicochemical properties derived from the protein sequences and employed machine-learning algorithms to examine potential candidates. This resulted in 24 targeted optimized ketoreductases (TOP-K) from 81,014 members. The experimental validation of select TOP-Ks demonstrated the correlation between the C-terminal lid-loop structure, enzyme flexibility and turnover rate on pro-pharmaceutical substrates.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 46,061
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences
Li, W.-Z., & Godzik, A. (2006) · Bioinform. · doi:10.1093/bioinformatics/btl158 · Cited by 10,996
Three-dimensional Epigenome Statistical Model: Genome-wide Chromatin Looping Prediction
Bkhetan, Z. A., & Plewczyński, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-23276-8 · Cited by 1,672
Kitagawa, M., Ara, T., Arifuzzaman, M., Ioka-Nakamichi, T., Inamoto, E., Toyonaga, H., & Mori, H. (2006) · DNA Research · doi:10.1093/dnares/dsi012 · Cited by 1,388
Short-chain dehydrogenases/reductases (SDR)
Jörnvall, H., Persson, B., Krook, M., Atrian, S., Gonzàlez‐Duarte, R., Jeffery, J., & Ghosh, D. (1995) · Biochemistry · doi:10.1021/bi00018a001 · Cited by 1,241
Catalytic promiscuity and the evolution of new enzymatic activities
O’Brien, P., & Herschlag, D. (1999) · Chemistry & Biology · doi:10.1016/s1074-5521(99)80033-7 · Cited by 731
Du, D., Tan, L., Wang, Y., Peng, B., Weinstein, J. N., Wondisford, F. E., Su, X., & Lorenzi, P. L. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2669-9 · Cited by 554
Adjustment of conformational flexibility is a key event in the thermal adaptation of proteins
Závodszky, P., Kardos, J., Svingor, Á., & Petsko, G. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7406 · Cited by 526
The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative
Persson, B., Kallberg, Y., Bray, J. E., Bruford, E. A., Dellaporta, S. L., Favia, A. D., Duarte, R. G., Jörnvall, H., Kavanagh, K. L., Kedishvili, N. Y., et al. (2008) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2008.10.040 · Cited by 397
Cited by
Sorted by citations
Niu, J., Ma, B., Shen, J., Zhu, H., Lu, Z., Lu, Z., Lü, F., & Ping, Z. (2024) · Food Microbiology · doi:10.1016/j.fm.2024.104676 · Cited by 15
Identification and Application of Novel Patulin-Degrading Enzymes from Bacillus subtilis 168
Niu, J., Zhu, H., Shen, J., Ma, B., Chi, H., Lu, Z., Lü, F., & Ping, Z. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c06999 · Cited by 9
Cancer to Cataracts: The Mechanistic Impact of Aldo-Keto Reductases in Chronic Diseases
Shanbhag, A. P., & Bhowmik, P. (2024) · The Yale Journal of Biology and Medicine · doi:10.59249/vtbv6559 · Cited by 4
Self-citationHou, X., Gu, J., Chen, J., Ullah, H., Mamtimin, T., Wang, X., Li, X., Jiang, Y., Fan, J., Han, H., et al. (2025) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2025.138486 · Cited by 3
Metadata
- Authors
- Shanbhag, A. P., Rajagopal, S., Ghatak, A., Katagihallimath, N., Subramanian, R., & Datta, S.
- Affiliations
- Bugworks Research India Pvt. Ltd., Bangalore, India
- Biomoneta Research Pvt. Ltd., Bangalore, India
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
- Corresponding author
- Datta, Santanu
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2023-06-19
- Volume
- 480
- Issue
- 13
- Pages
- 975-997
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W4381197802
- Cited by
- 5
- References
- 76
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Ministry of Science and Technology, India (BT/BIP0475/13/11, BT/PR13429/BRB/10/767/)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Enzyme Production and Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- short-chain dehydrogenase/reductase, ketoreductase, enzyme promiscuity, substrate-binding region, enzyme flexibility, chiral alcohol synthesis, FabG, physicochemical properties, machine learning prediction, turnover rate
- MeSH terms
- Amino Acid Sequence, Catalysis, High-Throughput Screening Assays
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
