Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds

Abstract

Freestanding nonproteinogenic amino acids have long been recognized for their antimetabolite properties and tendency to be uncovered to reactive functionalities by the catalytic action of target enzymes. By installing them regiospecifically into biogenic peptides and proteins, it may be possible to usher a new era at the interface between small molecule and large molecule medicinal chemistry. Site-selective protein functionalization offers uniquely attractive strategies for posttranslational modification of proteins. Last, but not least, many of the amino acids not selected by nature for protein incorporation offer rich architectural possibilities in the context of ribosomally derived polypeptides. This Review summarizes the biosynthetic routes to and metabolic logic for the major classes of the noncanonical amino acid building blocks that end up in both nonribosomal peptide frameworks and in hybrid nonribosomal peptide-polyketide scaffolds.

Keywords: biosynthesis; nonproteinogenic amino acids; nonribosomal peptides; polyketides.

Figure 1

Miraziridine A. Nonproteinogenic amino acids: red = (3S, 4S)-statine, blue = (2R, 3R)-aziridine-2,3-dicarboxylate, green = L-α-aminobutyrate, purple = (S)-vinyl-Arg. Hyperlink 2: Hypothetical biosynthesis of miraziridine A. Hyperlink 3: Biosynthesis of α-aminobutyric acid (Aba) in E. coli K-12. avtA: http://www.ncbi.nlm.nih.gov/protein/YP_491862.1 ilvA: http://www.ncbi.nlm.nih.gov/protein/CAA28577.1 Hyperlink 4: Biosynthesis of statine moiety of Thailandepsin E. Hyperlink 5: Biosynthesis of vinylogous alanine moiety of Jamaicamide B

Figure 2

Bottromycin A₂. Nonproteinogenic amino acids: red = (2S,3R)-3-methyl-Pro, blue = L-t-butyl-Gly, green = (2S,3S)-β-methyl-Phe, purple = (R)-methyl 3-amino-3-(thiazol-2-yl)propanoate.

Figure 3

Polymyxin B2, a stem-loop macrolactam. Nonproteinogenic amino acid: red = L-2,4-diaminobutyrate (2,4-DAB). Hyperlink 6: Biosynthesis of 2,4-diaminobutyrate (2,4-DAB) from aspartyl phosphate in Pseudomonas aeruginosa PAO1 Asd: http://www.ncbi.nlm.nih.gov/protein/AAC23936.1 PvdH: http://www.ncbi.nlm.nih.gov/protein/AAG05801.1

Figure 4

Callipeltin B, a Thr linked depsipeptide. Nonproteinogenic amino acids: red = (2R,3R)-β-methoxy-Tyr, blue = (2S,3S,4R)-3,4-dimethyl-5-oxo-Pro. Hyperlink 7: Anti-HIV marine cyclicdepsipeptides containing a β-methoxytyrosine moiety.

Figure 5

Daptomycin. Nonproteinogenic amino acids: red = L-kynurenine, blue = (3S,4S)-b-methylglutamate, green = L-ornithine. Hyperlink 8: Biosynthesis of kyneurinine.

Figure 6

Kutzneride 1, a cyclic hexa(depsi)peptide. Nonproteinogenic amino acids: red = dichloropyrroloindoline carboxylate, blue = L-O-methyl-Ser, green = (2R,3S)-β-hydroxy-Glu, purple = methylcyclopropyl-Gly (MeCPGly), orange = piperazate. Hyperlink 9: MecPGly formation in kutzneride biosynthesis. KtzA: http://www.ncbi.nlm.nih.gov/protein/157429059 KtzB: http://www.ncbi.nlm.nih.gov/protein/157429060 KtzC: http://www.ncbi.nlm.nih.gov/protein/157429061 KtzD: http://www.ncbi.nlm.nih.gov/protein/157429062 KtzF: http://www.ncbi.nlm.nih.gov/protein/157429064 Hyperlink 10: Piperazate formation in kutzneride biosynthesis. KtzI: http://www.ncbi.nlm.nih.gov/protein/157429067 KtzQ: http://www.ncbi.nlm.nih.gov/protein/157429075 KtzR: http://www.ncbi.nlm.nih.gov/protein/157429076 Hyperlink 11: Hypothetical SAM mediated O-methylation biosynthesis.

Figure 7

Surfactin, a β-hydroxycarboxylic lactone

Figure 8

Syringolin A. Nonproteinogenic amino acids: red = L-vinyl-Val, blue = L-Δ-3-Lysene. Hyperlink 12: Biosynthesis of vinylvaline and 3,4-dehydrolysine on the syringolin (syl) synthase.

Figure 9

Aryl ethers and aryl-aryl linkages in cyclic peptides. Nonproteinogenic amino acids: red = (2S,3R,4S)-3,4-dihydroxy-Arg, blue = Aryl ether (L-Tyr/(R)-β-Tyr), green = Aryl ether (L-(p-hydroxy)phenyl-Gyl/L-m-nitro-Tyr). Hyperlink 13: Hypothetical pathway for eurypamide biosynthesis.

Figure 10

Natural products containing L-Aeo. Nonproteinogenic amino acids: red = L-2-amino-8-oxo-9,10-decanoate (Aeo). Hyperlink 14: Hypothetical pathway for Aeo biosynthesis.

Figure 11

Natural products containing a capreomycidine moiety. Nonproteinogenic amino acids: red = β-Lys, blue = L-2,3-DAP, green = (E)-ureidodehydro-Ala, purple = capreomycidine and δ-hydroxycapreomycidine. Hyperlink 15: Formation of L-2,3-diaminopropionate (2,3-DAP) from L-serine in zwittermycin biosynthesis ZmaU: http://www.ncbi.nlm.nih.gov/protein/223047493

Figure 12

Echinocandin B. Nonproteinogenic amino acids: red = (2S,3S,4S)-3,4-dihydroxyhomo-Tyr, blue = (2S,4R)-4-hydroxy-Pro, green = (2R,4R,5R)-4,5-dihydroxy-Orn, purple = (2S,3S,4S)-3-hydroxy-4-methyl-Pro. Hyperlink 16: Two possible routes for the biosynthesis of L-3-methyl-4-hydroxy-Pro from L-leucine

Figure 13

Hormaomycin. Nonproteinogenic amino acids: red = Nitrocyclopropyl-Ala, blue = 5-chloro-1-hydroxypyrrole-2-carboxylate, green = (2S,3R)-β-methyl-Phe, purple = (2R,4R)-4-((Z)-propenyl)-Pro.

Figure 14

Mycosubtilin. Nonproteinogenic amino acid: red = (S)-β-aminostearate.

Figure 15

Microcystin LR. Nonproteinogenic amino acids: red = vinylogous β-Ala, blue = (2R,3S)-β-methylaspartate, green= dehydro-Ala.

Figure 16

Didemnin B. Nonproteinogenic amino acids: red = L-O-Me-Tyr, blue = (3S,4R,5S)-isostatine.

Figure 17

Vancomycin and Teicoplanin. Nonproteinogenic amino acids: red = (2R,3R)-m-chloro-(or β-hydroxy-m-chloro)Tyr aryl ether, blue = 3,5-dihydroxy-Tyr aryl ether, green = p-hydroxyphenyl-Gly aryl-aryl, purple =3,5-dihydroxyphenyl-Gly arly-aryl or aryl ether, orange = (2S,3R)-β-hydroxy-m-chloro-Tyr aryl ether. Hyperlink 21: Aryl-aryl and aryl ether crosslinking in vancomycin. Hyperlink 22: Aryl amino acid hydroxylation. Hyperlink 23: Chlorination of amino acids

Figure 18

Friulimicin. Nonproteinogenic amino acids: red = D-pipecolate, blue = β-methyl-Asp, green = 2,3-DAB.

Figure 19

Cyclosporin A. Nonproteinogenic amino acids: red = (2S,3R,4R)-(E)-butenylmethyl-Thr, blue = L-α-aminobutyrate.

Figure 20

Ramoplanin and Enduracidine. Nonproteinogenic amino acids: red = enduracididine, blue = D or L p-hydroxyphenyl-Gly, green = L-3,5-dichloro-4-hydroxyphenyl-Gly or 3-chloro-4-hydroxyphenyl-Gly (in 34), purple = D-Orn, orange = (2S,3S)-β-hydroxy-Asp.

Figure 21

Sanglifehrin A. Nonproteinogenic amino acids: red = L-piperazate, blue = L-meta-Tyr.

Figure 22

Alkyne and alkene containing amino acids. A. red = β,γ-olefins, B. blue = γ,δ and δ,ε-olefins. C. green = alkynes and an allene. D. purple = dienes.

Figure 23

Amino acids accessed through aldehyde intermediates. A. glutamyl and aspartyl phosphates. B. Paraherquamide A biosynthesis. Nonproteinogenic amino acids: blue = 5-oxo-Ile, red = β-Me-Pro, green= Ahp.

Figure 24

Aldehyde, imine, ketone, and diazo-containing amino acids. Nonproteinogenic amino acids: red = formyl-Gly, blue = 2-amino-3-ketobutyrate, green= α-diazoketone or α-diazoester, purple = acivicin.

Figure 25

Dapdiamides and anticapsin. Nonproteinogenic amino acids: red = L-2,3-DAP, blue = anticapsin.

Scheme 1

Biosynthesis of ribosomal versus nonribosomal peptides. ATP = adenosine triphosphate, AMP = adenosine monophosphate, PP_i = pyrophosphate, A domain = adenylation domain, T domain = thiolation (peptidyl carrier protein) domain, C domain = condensation domain.

Scheme 2

Tyrocidine and its NRPS. A = adenylation domain, T = thiolation (peptidyl carrier protein) domain, C = condensation domain, E = epimerase domain, TE = thioesterase domain.

Scheme 3

Epothilone C and rapamycin biosynthesis. A. NRPS-PKS pathway. B. PKS-NRPS pathway. Nonproteinogenic amino acids: red = 2-methylthiazole-4-carboxylate, blue = L-pipecolate. A. epoA: http://www.ncbi.nlm.nih.gov/protein/AAF62880.1 epoB: http://www.ncbi.nlm.nih.gov/protein/AAF62881.1 B. Hyperlink 1: L-pipecolate formation in rapamycin biosynthesis. rapL: http://www.ncbi.nlm.nih.gov/protein/987107

Scheme 4

p-Aminophenylalanine biosynthesis in the pristinamycin IA pathway. Nonproteinogenic amino acids: red = L-(p-amino)-Phe (9) and L-((p-(N,N-dimethylamino))-Phe (10). papA: http://www.ncbi.nlm.nih.gov/protein/AAC44866.1 papB: http://www.ncbi.nlm.nih.gov/protein/AAC44868.1 papC: http://www.ncbi.nlm.nih.gov/protein/AAC44867.1 papM: http://www.ncbi.nlm.nih.gov/protein/AAC44869.1

Scheme 5

Coronamate biosynthesis and incorporation in the coronatine pathway. Nonproteinogenic amino acids: red = (2R)-2-amino-3-(chloromethyl)pentanoic acid, blue = coronamate (11). CmaC: http://www.ncbi.nlm.nih.gov/protein/NP_794455.1

Scheme 6

Racemase and epimerase activity. A. PLP-dependent catalysis for racemization. B. acid-base catalysis for racemization. C. template-bound catalysis for racemization.

Scheme 7

Interconversion of α- and β-amino acids. A. MIO-mediated catalysis. B. Radical intermediate catalysis.

Scheme 8

C-methylation of amino acids at the β-position. A. SAM-mediated C-methylation. B. radical SAM-mediated C-methylation. Hyperlink 24: Polytheonamide B.

Scheme 9

Hydroxylation of amino acids. A. Metal-dependent hydroxylation. B. FAD-dependent hydroxylation.

Scheme 10

Pipecolate and piperazate biosynthesis. A. Proposed mechanism of pipecolate formation. B. Proposed mechanism of piperazate formation.

Scheme 11

Biosynthesis of cyclic guanidines. A. Biosynthesis of six-membered cyclic guanidines. B. Biosynthesis of five-membered cyclic guanidines. Nonproteinogenic amino acids: red = capreomycidine, blue = tubericidine, green = (2S,3S)-β-methyl-Phe, purple = β-hydroxyenduracididine, orange = enduracididine.

Scheme 12

Hybrid NRPS-PKS assembly lines. A. Isostatine assembly into didemnin B. Mechanism of statine biosynthesis. C. Vinylogous amino acid biosynthesis. Nonproteinogenic amino acids: (A) red = O-Me-Tyr, blue = isostatine; (B) red = statine; (C): red = vinyl-Val, blue = vinyl-Arg, green = vinyl-Tyr.

Scheme 13

Hoiamide and tubulysin biosynthesis. A. Tubu-tyrosine and tubu-phenylalanine biosynthesis. B. Mechanism of 4-amino-3-hydroxy-2,5-dimethylheptanoate biosynthesis Nonproteinogenic amino acids: red = 4-amino-3-hydroxy-2,5-dimethylheptanoate, blue = tubu-Tyr or tubu-Phe.

Scheme 14

Biosynthesis of polyketide precursors to amino acids. A. Biosynthesis of 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoate (Adda). B. Biosynthesis of butenylmethyl-Thr.

Scheme 15

Biosynthesis of homo-Tyr.

Hyperlink Scheme 1

L-pipecolate formation in rapamycin biosynthesis.^[1]

Hyperlink Scheme 2

Hypothetical biosynthesis of miraziridine A. Nonproteinogenic amino acids: red= statine, blue = Azd, green = Aba, purple = vinyl-Arg.

Hyperlink Scheme 3

Biosynthesis of α-aminobutyric acid (Aba) in E. coli K-12.^[2]

Hyperlink Scheme 4

Biosynthesis of statine moiety of Thailandepsin E.^[3]

Hyperlink Scheme 5

Biosynthesis of vinylogous alanine moiety of Jamaicamide B.^[4]

Hyperlink Scheme 6

Biosynthesis of 2,4-diaminobutyrate (2,4-DAB) from aspartyl phosphate in Pseudomonas aeruginosa PAO1.^[5]

Hyperlink Scheme 7

Anti-HIV marine cyclicdepsipeptides containing a β-methoxytyrosine moiety.^[6] Nonproteinogenic amino acids: red = β-methoxy-Tyr, blue= β-hydroxy-Tyr.

Hyperlink Scheme 8

Biosynthesis of kyneurinine.^[7]

Hyperlink Scheme 9

MecPGly formation in kutzneride biosynthesis.^[8]

Hyperlink Scheme 10

Piperazate formation in kutzneride biosynthesis.^[8] Nonproteinogenic amino acids: red = dichloropyrroloindoline carboxylate, blue = L-O-methyl-Ser, green = (2R,3S)-β-hydroxy-Glu, purple = methylcyclopropyl-Gly (MeCPGly), orange = γ-chloropiperazate.

Hyperlink Scheme 11

Hypothetical SAM mediated O-methylation biosynthesis.

Hyperlink Scheme 12

Biosynthesis of vinylvaline and 3,4-dehydrolysine on the syringolin (syl) synthase. Nonproteinogenic amino acids: red = L-vinyl-Val, blue = L-Δ-3-Lysene.

Hyperlink Scheme 13

Hypothetical pathway for eurypamide biosynthesis.^[11] Nonproteinogenic amino acids: red = (2S,3R,4S)-3,4-dihydroxy-Arg, blue = Aryl ether (L-Tyr/(R)-β-Tyr).

Hyperlink Scheme 14

Hypothetical pathway for Aeo biosynthesis.^[12]

Hyperlink Scheme 15

Formation of L-2,3-diaminopropionate (2,3-DAP) from L-serine in zwittermycin biosynthesis.^[13]

Hyperlink Scheme 16

Two possible routes for the biosynthesis of L-3-methyl-4-hydroxy-Pro from L-leucine.^[14]

Hyperlink Scheme 17

Hormaomycin biosynthesis.^[15] Nonproteinogenic amino acids: red = Nitrocyclopropyl-Ala, blue = 5-chloro-1-hydroxypyrrole-2-carboxylate, green = (2S,3R)-β-methyl-Phe, purple = (2R,4R)-4-((Z)-propenyl)-Pro.

Hyperlink Scheme 18

Propenylproline formation in hormaomycin biosynthesis.^[16]

Hyperlink Scheme 19

Proposed 5-chloropyrrole-2-carboxylate formation in hormaomycin biosynthesis.^[16]

Hyperlink Scheme 20

Two possible pathways for nitrocyclopropylalanine formation in hormaomycin biosynthesis.^[16]

Hyperlink Scheme 21

Aryl-aryl and aryl ether crosslinking in vancomycin.^[17,18] Nonproteinogenic amino acids: red = (2R,3R)-m-chloro-(or β-hydroxy-m-chloro)Tyr aryl ether, blue = 3,5-dihydroxy-Tyr aryl ether, green = p-hydroxyphenyl-Gly aryl-aryl, purple =3,5-dihydroxyphenyl-Gly arly-aryl or aryl ether, orange = (2S,3R)-β-hydroxy-m-chloro-Tyr aryl ether.

Hyperlink Scheme 22

Aryl amino acid hydroxylation. A. Aryl ring hydroxylation. B. Cβ-hydroxylation. Nonproteinogenic amino acids: red = m-Tyr, blue = β-hydroxy-m-Tyr.

Hyperlink Scheme 23

Chlorination of amino acids. A. γ-Halogenases. B. Chlorination of β-hydroxy-Tyr. Nonproteinogenic amino acids: red = (2R)-2-amino-3-(chloromethyl)pentanoic acid, blue = β-hydroxy-m-chloro-Tyr.

Hyperlink Figure 1

Polytheonamide B.^[19] Nonproteinogenic amino acids: red = t-butyl-Gly, blue = β-methyl-Ile, green = β-hydrox-Val, orange = β-hydrox-N-methyl-Asn or β-hydroxy-N-methyl-Gln, purple = (2R)-2-amino-3-methyl-3-(methylsulfinyl)butanoic acid. Also note the numerous N-methyl-Asn residues.

Hyperlink Scheme 24

Formation of aziridine carboxylate in azicemicin A biosynthesis.