Recent Advances in Biocatalysis for Drug Synthesis
Abstract
:1. Introduction
2. Biocatalysis for Drug Synthesis
2.1. Expansion of Product Spectrum
2.1.1. Natural Metabolism as Source of Enzymes and Biochemical Pathways
Amide Bond Formation Revisited
Engineered IREDs for Synthesis of Chiral Amines
Increasing the Usability of Fe2+/α-Ketoglutarate-Dependent Dioxygenases
Biocatalytic Scaffold Formation
2.1.2. Expansion of Product Spectrum by Engineered Biocatalysts, as Exemplarily Illustrated for Nonribosomal Peptide Synthetases
Enzyme | Source Organism | Modification | Biocatalyst | Substrate | Product | Process Performance | Reference |
---|---|---|---|---|---|---|---|
NRPS | Xenorhabdus bovienii | Artificial splitting of NRPS by inserting natural docking domains | Whole-cell | Amino acids | Xefoampeptides derivatives | Wild-type yield | [64] |
NRPS | Xenorhabdus; Photorhabdus | Introduction of exchange units | Whole-cell | Amino acids | Ambactin derivatives | - | [65,66] |
NRPS | Xenorhabdus; Photorhabdus; Bacillus | Introduction of exchange unit condensation domains | Whole-cell | Amino acids | GameXPeptide derivatives | - | [67] |
NRPS | Xenorhabdus nematophila; Photorhabdus luminescens | Introduction of synthetic zippers | Whole-cell | Amino acids | Xenotetrapeptide; GameXPeptide derivatives | Wild-type yield | [68] |
NRPS | Brevibacillus brevis | Using zinc fingers as guidance on ssDNA | Isolated enzyme | Amino acids | Gramicidin derivatives | - | [69] |
NRPS | Streptomycetes | Exchanging FSD that contains key active site residues within A domains | Whole-cell | Amino acids | Enduracididn derivatives | Wild-type yield | [70] |
2.2. Expanding Biocatalytic Capabilities in Diversification and Late-Stage Functionalization
Enzyme | Source Organism | Modification | Biocatalyst | Substrate | Product | Process Performance | Reference |
---|---|---|---|---|---|---|---|
CYP105D | Streptomyces platensis | Wild-type | E. coli cell lysate | Ritonavir | Hydroxy ritonavir | 58% conversion | [95] |
CYP107Z | Streptomyces platensis | Wild-type | E. coli cell lysate | Amitriptyline | Demethylated/dide-methylated amitriptyline | 53%/7% conversion | [95] |
P450 CxnD | Actinoplanes tsinanensis | Wild-type | Isolated enzyme (E. coli) | Chuangxinmycin precusor | Chuangxinmycin | - | [105] |
P450 BM3 variant | Bacillus megaterium | Directed evolution | E. coli cell lysate | Noscapine | Demethylated noscapine | 50% conversion | [106] |
P450 BM3 variant | Bacillus megaterium | Directed evolution | Isolated enzyme (E. coli) | Testosterone | Hydroxy testosterone | ≤76% conversion | [107] |
CYP154E1 variant | Thermobifida fusca | Directed evolution | Whole-cell (E. coli) | (R)-Ketamine | (2R,6R)-Hydroxynorketamine | ≤85% product | [108] |
CYP-sb21 | Sebekia benihana | Directed evolution | Isolated enzyme (E. coli) | Cyclosporin A | Hydroxy cyclosporin A | ≤94.6% substrate conversion | [109] |
P450 TamI | Streptomyces sp. 307-9 | Directed evolution | Isolated enzyme (E. coli) | Tirandamycin | Hydroxy tirandamycin | New tirandamycin congeners | [110] |
AaeUPO | Agrocybe aegerita | Wild-type | Isolated enzyme | trans-Stilbene | 4,4′-Dihydroxy-trans-stilbene | 94% product yield | [111] |
MroUPO | Marasmius rotula | Wild-type | Isolated enzyme | Clopidogrel | 2-Oxo-clopidogrel | 46% product | [112] |
MroUPO | Marasmius rotula | Wild-type | Isolated enzyme | 2-Oxo-prasugrel | Active prasugrel metabolite | 34% product | [112] |
UPO SoLo | Agrocybe aegerita | Evolved AaeUPO variant | Isolated enzyme | Propranolol | 5′-Hydroxypropranolol | 15% isolated yield | [113] |
UPO JaWa | Agrocybe aegerita | Evolved AaeUPO variant | Isolated enzyme | Dextromethorphan | O-Desmethylnaproxen | 82% product | [114] |
UPO SoLo-D241G | Agrocybe aegerita | Evolved AaeUPO variant | Isolated enzyme | Naproxen | Hydroxy tolbutamide | 20% product | [114] |
AaeUPO | Agrocybe aegerita | Wild-type | Isolated enzyme | Tolbutamide | 4-Hydroxymethyl-tolbutamide | 57% product | [114] |
Halogenase DklH | Frankia alni | Wild-type | Whole-cell (Streptomyces albus) | Luteolin | Dichloroluteolin | 86% product | [115] |
Halogenase WelO5* CA2 | Hapalosiphon welwitschii | Evolved WelO5* variant | E. coli cell lysate | Martinelline-derived substrate | Hydroxylated product | 30% isolated yield | [116] |
Halogenase WelO5* VLA | Hapalosiphon welwitschii | Evolved WelO5* variant | Isolated enzyme | Soraphen A | Mono-chlorinated product | 50% conversion | [117] |
2.3. Synthetic Enzyme Cascades
Enzyme | Source Organism | Modification | Biocatalyst | Substrate | Product | Process Performance | Reference |
---|---|---|---|---|---|---|---|
IRED; KRED | Diverse | Directed evolution (one enzyme) | Isolated enzymes | Amine tranylcypromine sulfate, alcohol precursor | Protected GSK-2879552 | 5 g scale with 48.3% yield, 99.5%-ee, 97.9% purity | [34] |
Nov435; MTR kinase; UP; AcK; catalase; POX | Diverse | Directed evolution (two enzymes) | Isolated enzymes | Ribose, uracil | Molnupiravir | 69% overall yield | [149] |
GOase; HRP; catalase; PanK; AcK; PNP; PPM; DERA; SP | Diverse | Directed evolution (five enzymes) | Isolated enzymes | 2-Ethynylglycerol | Islatravir | 51% overall yield | [141] |
ThiM; IPK; IDI; GPPS; ADK; AcKA; PTA; MdcA; AAE3; OLS; OAC; CBGA synthase | Diverse | One engineered enzyme by Rosetta design [151] | Isolated enzymes | Isoprenol, acetylphosphate, malonate, butyrate/hexanoate | Cannabigerolic acid (CBGA); cannabigerovarinic acid (CBGVA) | 480 mg L−1 (CBGA), 580 mg L−1 (CBGVA) | [152] |
ADK; 2 PPK2; cGAS | Diverse | - | Isolated enzymes | Adenosine, GTP | 2′3′-cGAMP | 0.08 mol per mol adenosine | [153] |
GK; AK; AcK; cGAS | Diverse | Directed evolution (four enzymes) | Isolated enzymes | Nucleotide monothiophosphates | MK-1454 | 62% isolated yield | [154] |
3. Conclusion and Outlook
Author Contributions
Funding
Conflicts of Interest
References
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Enzyme | Source Organism | Modification | Biocatalyst | Substrate | Product | Process Performance | Reference |
---|---|---|---|---|---|---|---|
4-Chlorobenzoate ATP-dependent CoA ligase (CBL) and serotonin hydroxycinnamoyltransferase (66CaAT) | Alcaligenes sp.; Capsicum annuum | - | Whole-cell | 6-Chloronicotinic acid; neopentylamine | 6-Chloro-N-neopentylnicotinamide (losmapimod key intermediate) | 83% conversion, 74% isolated yield | [16] |
ATP-dependent amide bond synthetase McbA | Marinactinospora thermotolerans | - | Isolated enzyme | 4-Chlorobenzoic acid; 4-(2-aminoethyl) morpholine | Moclobemide | 70% conversion, 64% isolated yield | [17] |
Carboxylic acidreductase CARmm-A | Mycobacterium marinum | Truncated enzyme variant | Isolated enzyme | 3,4,5-trimethoxycinnamic acid; piperazine acetic acid pyrrolidine | Cinepazide | 18% isolated yield | [18] |
SpRedAm-R3-V6 | Streptomyces purpureus | Engineered variant (four amino acid exchanges) | Isolated enzyme | Isopropyl 3-oxocyclobutane-1-carboxylate; monomethylamine | Isopropyl 3-(methylamino) cyclobutane-1-carboxylate (abrocritinib key intermediate) | 60 g L−1 d−1, purity >99.5%, selectivity >99:1 cis:trans | [19] |
Lysine dioxygenase (KDO) | Catenulispora acidiphila | Immobilization with HaloTag® | Isolated enzyme | l-Lysine | (3S)-3-Hydroxy- l-lysine | 32.4 g L−1, 100 g L−1 h−1 per gimmobilized enzyme | [20] |
Proline hydroxylase SmP4H | Sinorhizobium meliloti | Engineered variant (two amino acid exchanges) | Isolated enzyme | l-Homophenylalanine | γ-Hydroxylated l-homophenylalanine | kcat 1.680 ± 0.068 min−1, 35.3% yield | [21] |
Proline hydroxylase SmP4H | Sinorhizobium meliloti | One amino acid exchange (W40Y) | Isolated enzyme | l-Homophenylalanine | 3,4-Desaturated l-homophenylalanine | kcat 0.83 ± 0.02 min−1, 50.7% yield | [21] |
Proline hydroxylase SmP4H | Sinorhizobium meliloti | Engineered variant (six amino acid exchanges) | Cell lysate | l-Proline | cis-3-Chloro- l-proline | 4.86 ± 0.16% yield, >98.5%-ee | [22] |
Norcoclaurine synthase (tfNCS) | Thalictrum flavum | Directed evolution | Cell lysate | Aromatic β-amine; ketone | Tetrahydroisoquinolines | 59-79% conversion 74-90%-ee | [23] |
Methyl transferase PsmD; halide methyl transferase (ctHMT) | Streptomyces griseofuscus; Chloracidobacterium thermophilum | - | Isolated enzymes including SAM- cofactor recycling | Tryptamines | Physostigmines | 13-84% isolated yield >99%-ee | [24] |
Terpene cyclase (AacSHC) | Alicyclobacillus acidocaldarius | Semi-rational design | Isolated enzyme | Geranyl acetone | γ-Dihydroionone | 89% isolated yield, >99%-ee | [25] |
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Kinner, A.; Nerke, P.; Siedentop, R.; Steinmetz, T.; Classen, T.; Rosenthal, K.; Nett, M.; Pietruszka, J.; Lütz, S. Recent Advances in Biocatalysis for Drug Synthesis. Biomedicines 2022, 10, 964. https://doi.org/10.3390/biomedicines10050964
Kinner A, Nerke P, Siedentop R, Steinmetz T, Classen T, Rosenthal K, Nett M, Pietruszka J, Lütz S. Recent Advances in Biocatalysis for Drug Synthesis. Biomedicines. 2022; 10(5):964. https://doi.org/10.3390/biomedicines10050964
Chicago/Turabian StyleKinner, Alina, Philipp Nerke, Regine Siedentop, Till Steinmetz, Thomas Classen, Katrin Rosenthal, Markus Nett, Jörg Pietruszka, and Stephan Lütz. 2022. "Recent Advances in Biocatalysis for Drug Synthesis" Biomedicines 10, no. 5: 964. https://doi.org/10.3390/biomedicines10050964
APA StyleKinner, A., Nerke, P., Siedentop, R., Steinmetz, T., Classen, T., Rosenthal, K., Nett, M., Pietruszka, J., & Lütz, S. (2022). Recent Advances in Biocatalysis for Drug Synthesis. Biomedicines, 10(5), 964. https://doi.org/10.3390/biomedicines10050964