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Information on EC 2.3.2.21 - cyclo(L-tyrosyl-L-tyrosyl) synthase
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EC Tree
2.3.2.21 cyclo(L-tyrosyl-L-tyrosyl) synthaseIUBMB Comments
The reaction proceeds following a ping-pong mechanism forming a covalent intermediate between an active site serine and the first L-tyrosine residue . The protein, from the bacterium Mycobacterium tuberculosis, also forms small amounts of cyclo(L-tyrosyl-L-phenylalanyl) .
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The enzyme appears in viruses and cellular organisms
Synonyms
rv2275, cyclodityrosine synthetase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CDPS
cyclo(L-tyrosyl-L-tyrosyl) synthase
cyclodipeptide synthase
cyclodityrosine synthetase
cYY synthase
Rv2275
cYY synthase
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Rv2275
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2 L-tyrosyl-tRNATyr = 2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
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2 L-tyrosyl-tRNATyr = 2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
reaction proceeds via a covalent intermediate in which L-tyrosine is transferred from Tyr-tRNATyr to an active site serine, S88, by transesterification and with residue E233 serving as a critical base catalyzing dipeptide bond formation
2 L-tyrosyl-tRNATyr = 2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
reaction proceeds via a covalent intermediate in which L-tyrosine is transferred from Tyr-tRNATyr to an active site serine, S88, by transesterification and with residue E233 serving as a critical base catalyzing dipeptide bond formation
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SYSTEMATIC NAME
IUBMB Comments
L-tyrosyl-tRNATyr:L-tyrosyl-tRNATyr tyrosyltransferase (cyclizing)
The reaction proceeds following a ping-pong mechanism forming a covalent intermediate between an active site serine and the first L-tyrosine residue [2]. The protein, from the bacterium Mycobacterium tuberculosis, also forms small amounts of cyclo(L-tyrosyl-L-phenylalanyl) [1].
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 L-tyrosyl-tRNALeu
2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
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?
L-tyrosyl-tRNATyr + L-phenylalanyl-tRNAPhe
tRNATyr + tRNAPhe + cyclo(L-tyrosyl-L-phenylalanyl)
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?
2 L-tyrosyl-tRNATyr
2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
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?
2 L-tyrosyl-tRNATyr
2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
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?
additional information
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cyclodipeptides synthesized by gene product Rv2275 always contain L-tyrosine
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?
additional information
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Rv2275 is established as a CDPS that catalyzes formation of cyclo(L-tyrosyl-L-tyrosyl) as its major product, along with a handful of minor products containing tyrosine
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additional information
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cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides. Catalytic mechanism, overview
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additional information
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cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides. Catalytic mechanism, overview
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additional information
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cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides. Catalytic mechanism, overview
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 L-tyrosyl-tRNATyr
2 tRNATyr + cyclo(L-tyrosyl-L-tyrosyl)
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?
L-tyrosyl-tRNATyr + L-phenylalanyl-tRNAPhe
tRNATyr + tRNAPhe + cyclo(L-tyrosyl-L-phenylalanyl)
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?
additional information
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Rv2275 is established as a CDPS that catalyzes formation of cyclo(L-tyrosyl-L-tyrosyl) as its major product, along with a handful of minor products containing tyrosine
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Tuberculosis
Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog.
Tuberculosis
The structure and mechanism of the Mycobacterium tuberculosis cyclodityrosine synthetase.
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
metabolism
comparison of different CDPS-containing biosynthetic pathways, enzyme Rv2275 is involved in the mycocyclosin biosynthetic pathway, overview. Rv2275 is established as a CDPS that catalyzes formation of cyclo(L-tyrosyl-L-tyrosyl) as its major product, along with a handful of minor products containing tyrosine
physiological function
cyclodipeptide synthases (CDPSs) are recognized catalysts of 2,5-diketopiperazine (DKP) assembly, employing two aminoacyl-tRNAs (aa-tRNAs) as substrates. Representative 2,5-diketopiperazine (DKP) natural products and bioactivities, overview
additional information
evolution
CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold. The XYP and NYH motifs correspond to two structural solutions to facilitate the reactivity of the catalytic serine residue. The CDPS from Mycobacterium tuberculosis belongs to the NYH subfamily
evolution
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the enzyme belongs to the CDPS family, NYH subfamily containing the catalytic residues Asn40, Tyr178, and His203 (AlbC numbering). The exception of Tyr196, CDPS-Np shares identical amino acids in other positions with one or more CDPSs in pocket P1
evolution
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CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold. The XYP and NYH motifs correspond to two structural solutions to facilitate the reactivity of the catalytic serine residue. The CDPS from Mycobacterium tuberculosis belongs to the NYH subfamily
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evolution
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CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold. The XYP and NYH motifs correspond to two structural solutions to facilitate the reactivity of the catalytic serine residue. The CDPS from Mycobacterium tuberculosis belongs to the NYH subfamily
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additional information
CDPSs structure comparisons, comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold, overview. The CDPS adopts a common architecture with a monomer built around a Rossmann fold domain that displays structural similarity to the catalytic domain of the two class Ic aminoacyl-tRNA synthetases (aaRSs), TyrRS and TrpRS. It contains a deep surface-accessible pocket P1, the location of which corresponds to that of the aminoacyl-binding pocket of the two aaRSs. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. Despite these differences, the key catalytic residues (S37, Y202, Y178 and E182, AlbC numbering) are conserved in all CDPSs and have a same location in the catalytic centre of the enzymes. Residues belonging to the signature sequences play parallel roles in the two subfamilies, contributing to the positioning of the catalytic serine and of the crucial Y202 residue. The mode of action of the signature residues however differs, with a more complex network of hydrogen bonds in NYH enzymes. Notably, the signature residues are located in the two catalytic loops at the switch point between the two halves of the Rossmann fold
additional information
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strong influence on product accumulation of the amino acid residues in pocket P1
additional information
the CDPS catalytic mechanism entails initial covalent tethering of the aminoacyl moiety from the first aa-tRNA substrate onto a conserved active site serine (Ser) residue. Nucleophilic attack of the amino nitrogen on the carbonyl carbon from the second aa-tRNA substrate yields the first peptide bond. The resulting enzyme-linked dipeptidyl intermediate then undergoes intramolecular peptide bond formation to yield the DKP group with concomitant release from the active site. The two aa-tRNA substrates bind at different sites of the CDPS
additional information
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CDPSs structure comparisons, comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold, overview. The CDPS adopts a common architecture with a monomer built around a Rossmann fold domain that displays structural similarity to the catalytic domain of the two class Ic aminoacyl-tRNA synthetases (aaRSs), TyrRS and TrpRS. It contains a deep surface-accessible pocket P1, the location of which corresponds to that of the aminoacyl-binding pocket of the two aaRSs. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. Despite these differences, the key catalytic residues (S37, Y202, Y178 and E182, AlbC numbering) are conserved in all CDPSs and have a same location in the catalytic centre of the enzymes. Residues belonging to the signature sequences play parallel roles in the two subfamilies, contributing to the positioning of the catalytic serine and of the crucial Y202 residue. The mode of action of the signature residues however differs, with a more complex network of hydrogen bonds in NYH enzymes. Notably, the signature residues are located in the two catalytic loops at the switch point between the two halves of the Rossmann fold
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additional information
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CDPSs structure comparisons, comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold, overview. The CDPS adopts a common architecture with a monomer built around a Rossmann fold domain that displays structural similarity to the catalytic domain of the two class Ic aminoacyl-tRNA synthetases (aaRSs), TyrRS and TrpRS. It contains a deep surface-accessible pocket P1, the location of which corresponds to that of the aminoacyl-binding pocket of the two aaRSs. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. The XYP and the NYH architectures appear as two solutions to stabilize Y202 and facilitate the reactivity of the catalytic S37. Despite these differences, the key catalytic residues (S37, Y202, Y178 and E182, AlbC numbering) are conserved in all CDPSs and have a same location in the catalytic centre of the enzymes. Residues belonging to the signature sequences play parallel roles in the two subfamilies, contributing to the positioning of the catalytic serine and of the crucial Y202 residue. The mode of action of the signature residues however differs, with a more complex network of hydrogen bonds in NYH enzymes. Notably, the signature residues are located in the two catalytic loops at the switch point between the two halves of the Rossmann fold
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CDTS_MYCTO
Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
289
0
31612
Swiss-Prot
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CDTS_MYCTU
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
289
0
31612
Swiss-Prot
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 2.0 A resolution. Gene product Rv2275 is structurally related to the class Ic aminoacyl-tRNA-synthetase family of enzymes. Reaction proceeds via a covalent intermediate in which L-tyrosine is transferred from Tyr-tRNATyr to an active site serine, S88, by transesterification and with residue E233 serving as a critical base catalyzing dipeptide bond formation
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
T82A
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
T82A/Y196F
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
T82A/Y196L
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
T82V
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
T82V/Y196F
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site-directed mutagenesis, an 8fold increase in product formation for cyclo(L-tyrosyl-L-tyrosyl) and 10fold for cyclo(L-tyrosyl-L-phenylalanyl) are detected in the double mutant compared to the wild-type, cYY/cYF product ratio compared to wild-type enzyme
T82V/Y196L
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
Y196F
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
Y196L
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site-directed mutagenesis, cYY/cYF product ratio compared to wild-type enzyme
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Rv2275, recombinant expression in Escherichia coli strain BL21AI, subcloning in Escherichia coli strain DH5alpha
recombinant overexpression of His-tagged wild-type and mutant enzymes in Escherichia coli resulted in the formation of cyclo-(L-Tyr-L-Tyr) as the minor and cyclo-(L-Tyr-L-Phe) as the major products
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
synthesis
synthesis
cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines
synthesis
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cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines
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synthesis
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cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Gondry, M.; Sauguet, L.; Belin, P.; Thai, R.; Amouroux, R.; Tellier, C.; Tuphile, K.; Jacquet, M.; Braud, S.; Courcon, M.; Masson, C.; Dubois, S.; Lautru, S.; Lecoq, A.; Hashimoto, S.; Genet, R.; Pernodet, J.L.
Cyclodipeptide synthases are a family of tRNA-dependent peptide bond-forming enzymes
Nat. Chem. Biol.
5
414-420
2009
Mycobacterium tuberculosis
brenda
Vetting, M.W.; Hegde, S.S.; Blanchard, J.S.
The structure and mechanism of the Mycobacterium tuberculosis cyclodityrosine synthetase
Nat. Chem. Biol.
6
797-799
2010
Mycobacterium tuberculosis (P9WPF9), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPF9)
brenda
Brockmeyer, K.; Li, S.M.
Mutations of residues in pocket P1 of a cyclodipeptide synthase strongly increase product formation
J. Nat. Prod.
80
2917-2922
2017
Nocardiopsis prasina
brenda
Bourgeois, G.; Seguin, J.; Babin, M.; Belin, P.; Moutiez, M.; Mechulam, Y.; Gondry, M.; Schmitt, E.
Structural basis for partition of the cyclodipeptide synthases into two subfamilies
J. Struct. Biol.
203
17-26
2018
Mycobacterium tuberculosis (P9WPF9), Mycobacterium tuberculosis H37Rv (P9WPF9), Mycobacterium tuberculosis ATCC 25618 (P9WPF9)
brenda
Borgman, P.; Lopez, R.; Lane, A.
The expanding spectrum of diketopiperazine natural product biosynthetic pathways containing cyclodipeptide synthases
Org. Biomol. Chem.
17
2305-2314
2019
Mycobacterium tuberculosis (P9WPF9)
brenda
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Release 2023.1 (January 2023)
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