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Review
. 2021 Jul 21;38(7):1362-1407.
doi: 10.1039/d0np00064g.

Identification and characterization of enzymes involved in the biosynthesis of pyrimidine nucleoside antibiotics

M McErlean  1 , X Liu  1 , Z Cui  1 , B Gust  2 , S G Van Lanen  1
Affiliations
Review

Identification and characterization of enzymes involved in the biosynthesis of pyrimidine nucleoside antibiotics

M McErlean et al. Nat Prod Rep. .

Abstract

Covering: up to September 2020 Hundreds of nucleoside-based natural products have been isolated from various microorganisms, several of which have been utilized in agriculture as pesticides and herbicides, in medicine as therapeutics for cancer and infectious disease, and as molecular probes to study biological processes. Natural products consisting of structural modifications of each of the canonical nucleosides have been discovered, ranging from simple modifications such as single-step alkylations or acylations to highly elaborate modifications that dramatically alter the nucleoside scaffold and require multiple enzyme-catalyzed reactions. A vast amount of genomic information has been uncovered the past two decades, which has subsequently allowed the first opportunity to interrogate the chemically intriguing enzymatic transformations for the latter type of modifications. This review highlights (i) the discovery and potential applications of structurally complex pyrimidine nucleoside antibiotics for which genetic information is known, (ii) the established reactions that convert the canonical pyrimidine into a new nucleoside scaffold, and (iii) the important tailoring reactions that impart further structural complexity to these molecules.

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Figures

Figure 1.
Figure 1.
Structures of representative nucleoside antibiotics of the peptidyl uridine family.
Figure 2.
Figure 2.
Biosynthesis of the peptidyl uridine family of nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession numbers are napsamycin (nps) from Streptomyces sp. DSM 5940, HQ287563; pacidamycin (pac) from Streptomyces coeruleorubidus strain NRRL 18370, HM855229; and sansanmycin (ssa) from Streptomyces sp. SS, KC188778. (B) Pathway for the biosynthesis of the nucleoside core. (C) Pathways for the biosynthesis of the pseudopeptide and attachment to the nucleoside core. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. PLP, pyridoxal-5’-phosphate; DABA, diaminobutyric acid; A, adenylation; C, condensation, T, thiolation.
Figure 3.
Figure 3.
Generation of unnatural pacidamycins. A combination of combinatorial biosynthesis via heterologous expression of the foreign halogenase-encoding gene prnA and semisynthesis via Suzuki-Miyaura coupling was used to generate Trp-substituted pacidamycins.
Figure 4.
Figure 4.
Structures of representative nucleoside antibiotics of the lipouridine family. *The sulfate was initially assigned to R2; however, recent data is consistent with sulfonation at R1 (ref. 312).
Figure 5.
Figure 5.
Biosynthesis of the lipouridine family of nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession numbers are caprazamycin (cpz) from Streptomyces sp. MK730F-62F2, FJ490409 and HM051054; liposidomycin (lpm) from Streptomyces griseoporeus, GU219978; A-90289 (lip) from Streptomyces sp. SANK 60405, AB530986; muraminomicin (mra) from Streptosporangium amethystogenes SANK 60709, AB746937. (B) Pathway for the biosynthesis of the disaccharide core. (C) Pathway for the biosynthesis of the diazapenone ring and subsequent acylation steps. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. Orthologs of the respective caprazamycin proteins are indicated in parenthesis. X (90-93) indicated the different saturated or unsaturated aliphatic chains shown in Figure 4. αKG, α-ketoglutarate; PPi, inorganic pyrophosphate; Succ., succinate; 2-oxo-MTB, 2-oxo-4-methylthio-butanoate; MTA, methylthioadenosine; AdoMet, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine; PLP, pyridoxal-5’-phosphate; CoA, coenzyme A.; β-ha-CoA β-hydroxyacyl-CoA. *Respective homologs are LpmH, I, R, X, and Y; LipG, H, Q, W, and X; Mra18, 17, 13, 7, and 6.
Figure 6.
Figure 6.
Sulfonation mechanism using a novel polyketide as a sulfate shuttle. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes.
Figure 7.
Figure 7.
Structures of representative muraymycins and sphaerimicin A.
Figure 8.
Figure 8.
Biosynthesis of the muraymycin nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession numbers are muraymycin (mur) from Streptomyces sp. NRRL 30471, HQ257512; and sphaerimicin (sph) from Sphaerisporangium sp. SANK 60911, AB830104. (B) Pathway for the biosynthesis and convergence of the disaccharide core and pseudo-tripeptide. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. A, adenylation; C, condensation; T, thiolation; MTA, methylthioadenosine; AdoMet, S-adenosyl-l-methionine; PLP, pyridoxal-5’-phosphate.
Figure 9.
Figure 9.
Structure of jawsamycin and U-106305.
Figure 10.
Figure 10.
Biosynthesis of jawsamycin. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is jawsamycin (jaw) from Streptomyces roseoverticillatus HP-891, AB920328. (B) Pathway for the biosynthesis and convergence of the disaccharide core and pseudo-tripeptide. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. aKG, a-ketoglutarate; Succ., succinate; ACP, acyl carrier protein; 2-oxo-MTB, 2-oxo-4-methylthio-butanoate; PLP, pyridoxal-5’-phosphate.
Figure 11.
Figure 11.
Structures of the capuramycin family of nucleoside antibiotics.
Figure 12.
Figure 12.
Biosynthesis of the capuramycin family of nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession number are A-500359s (orf) from Streptomyces griseus SANK 60196, AB476988; A-503083s (cap) from Streptomyces sp. SANK 62799, AB538860; and A-102395 (cpr) from Amycolatopsis sp. SANK 60206, KP995196. (B) Pathways for the biosynthesis and convergence of the nucleoside core, the unsaturated hexuronic acid, and aminocaprolactam. The aminocaprolactam is attached via an unusual transacylation reaction catalyzed by ORF24 (CapW or Cpr27), wherein the methyl ester is converted to an amide. (C) Pathway for the biosynthesis of the polyamide component found in A-102395. Proteins labelled in bold blue have been functionally assigned using recombinant enzymes. Orthologs of the respective A-500359 biosynthetic proteins are indicated in parenthesis. PLP, pyridoxal-5’-phosphate; DABA, diaminobutyric acid; A, adenylation; C, condensation, T, thiolation. Abbreviations are αKG, α-ketoglutarate; PPi, inorganic pyrophosphate; Succ., succinate; PLP, pyridoxal-5’-phosphate; AdoMet, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine; A, adenylation; C, condensation, T, thiolation; ACP, acyl carrier protein.
Figure 13.
Figure 13.
Proposed mechanism of PLP-dependent 136:O2 monooxygenase-decarboxylase Cap15.
Figure 14.
Figure 14.
Structures of the tunicamycin family of nucleoside antibiotics. The unique tunicamine component is highlighted in blue.
Figure 15.
Figure 15.
Biosynthesis of tunicamycins. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is tunicamycin (tun) from Streptomyces chartreusis NRRL 3882, HQ111437. (B) Pathway for the biosynthesis of the trisaccharide core and subsequence acylation/deacylation steps. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes; the structure of TunA [Protein Data Bank (PDB) 3VPS] has been solved. PPi, inorganic pyrophosphate; AdoMet, S-adenosyl-l-methionine.
Figure 16.
Figure 16.
Comparison of the mechanisms for 4,6-dehydratases and TunA. Depicted in blue are catalytic residue conserved between the two enzymes. The last step in the mechanism for 4,6-dehydratses is shown with dashed areas and unique residues in red.
Figure 17.
Figure 17.
Structure of A-94964.
Figure 18.
Figure 18.
Biosynthesis of A-94964. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is A-94964 (anb) from Streptomyces sp. SANK 60404, LC431526. (B) Pathway for the biosynthesis of the nucleoside core and acylation with a polyketide putatively derived from the indicated polyketide synthase. T, thiolation; ER, enoylreductase; KS, ketosynthase; AT, acyltransferase; KR, ketoreductase; DH, dehydratase.
Figure 19.
Figure 19.
Structures of nikkomycin and polyoxin family of nucleoside antibiotics.
Figure 20.
Figure 20.
Biosynthesis of the nikkomycin and polyoxin family of nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession number are nikkomycin (nik) from Streptomyces tendae Tü 901, AJ250581, AJ250878, AJ251438, Y18574; nikkomycin (san) from Streptomyces aureochromogenes, AF322179, AF469956, MF055656; polyoxin (pol) from Streptomyces cacaoi var. asoensis, EU158805.(B) Pathway for the biosynthesis of the imidazolinone base found in the nikkomycin X series. (C) Pathway for the biosynthesis of the nucleoside core. During the conversion of 223 to 225, C3 of phosphoenolpyruvate (indicated with l) is retained. (D) Pathway for the biosynthesis of the nonproteinogenic amino acid component of nikkomycins and attachment to nucleoside core. (E) Pathway for the biosynthesis of the nonproteinogenic amino acid component of polyoxins and attachment to nucleoside core. Proteins labelled in bold have been functionally assigned in vitro using recombinant enzymes; the structures of NikD (PDB 3VPS) and NikO (PDB 4FQD) have been solved. Orthologs of the respective nikkomycin biosynthetic proteins are indicated in parenthesis. #, MbtH-like protein; A, adenylation; T, thiolation; TE, thioesterase; AMT, aminotransferase; αKG, α-ketoglutarate; Succ., succinate; αKB, α-ketobutyrate; PRPP, phosphoribosylpyrophosphate; PEP, phosphoenolpyruvate; dA, 5’-deoxyadenosine; PPi, inorganic pyrophosphate; CoA, coenzyme A.
Figure 21.
Figure 21.
Mechanism of NikJ and PolH. Abbreviations are AdoMet, S-adenosyl-l-methionine; 5-dA, 5’-deoxyadenosinie.
Figure 22.
Figure 22.
Structure of pseudouridimycin.
Figure 23.
Figure 23.
Biosynthesis of pseudouridimycin. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is pseudouridimycin (pum) from Streptomyces sp. ID38640, MG266907. (B) Pathway for the biosynthesis of the nucleoside core and subsequent acylation steps. Oxa, oxaloacetate
Figure 24.
Figure 24.
Structure of albomycins.
Figure 25.
Figure 25.
Biosynthesis of albomycins. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is albomycin (abm) from Streptomyces sp. ATCC 700974, JN252488. (B) Pathway for the biosynthesis of the nucleoside core. (C) Pathway for the biosynthesis of the tripeptide siderophore component and subsequent acylation to the nucleoside core. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. PLP, pyridoxal-5’-phosphate; AdoMet, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine; PPi, inorganic pyrophosphate; dA, 5’-deoxyadenosine; CoA, coenzyme A; C, condensation; A, adenylation; T, thiolation.
Figure 26.
Figure 26.
Structures of the amicetin family of nucleoside antibiotics.
Figure 27.
Figure 27.
Biosynthesis of amicetin. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is amicetin (ami) from Streptomyces vinaceusdrappus strain NRRL 2363, HM748814. (B) Pathway for the biosynthesis of the nucleoside core and subsequent acylation of the base. (C) Pathway for the biosynthesis of TDP-amicetose and TDP-amosamine. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes. PLP, pyridoxal-5’-phosphate; AdoMet, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine; PPi, inorganic pyrophosphate; THF, N5,N10-methylene tetrahydrofolic acid.
Figure 28.
Figure 28.
Structures of the blasticidin family of nucleoside antibiotics. (A) Structures of related compounds isolated from different strains. (B) Structures of biosynthetic precursors or shunt products isolated from the blasticidin producing strain.
Figure 29.
Figure 29.
Biosynthesis of the blasticidin family of nucleoside antibiotics. (A) Genetic organization of the biosynthetic gene clusters. NCBI accession number are blasticidin (bls) from Streptomyces griseochromogenes, AY196214; mildiomycin (mil) from Streptoverticillum remofaciens ZJU5119, JN999998; and arginomycin (arg) from Streptomyces arginensis, KC181124.(B) Pathway for the biosynthesis of the nucleoside core. (C) Pathway for the biosynthesis of the nonproteinogenic amino acid component of blasticidin and attachment to the nucleoside core. (D) Pathway for the biosynthesis of the nonproteinogenic amino acid component of arginomycin and mildiomycin and attachment to the nucleoside core. Proteins labelled in bold blue have been functionally assigned in vitro using recombinant enzymes; the structures of BlsM (PDB 5VTO), MilA (PDB 5JNH), and MilB (PDB 4OHR) have been solved. Orthologs of the respective biosynthetic proteins are indicated in parenthesis. 5hm-CMP, 5-hydroxymethyl-CMP; AdoMet, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine; PPi, inorganic pyrophosphate.
Figure 30.
Figure 30.
Structures of the gougerotin family of nucleoside antibiotics.
Figure 31.
Figure 31.
Biosynthesis of gougerotin. (A) Genetic organization of the biosynthetic gene cluster. NCBI accession number is gougerotin (gou) from Streptomyces graminearus strain AS4.506, JQ307220. (B) Pathway for the biosynthesis of the nucleoside core. (C) Pathway for the biosynthesis of the amino acid component and subsequent acylation to the nucleoside core.
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