Tet(M)-promoted release of tetracycline from ribosomes is GTP dependent
Open accessAbstract
Tet(M) protein, which displays homology to elongation factor G (EF-G), interacts with the protein biosynthetic machinery to render this process resistant to tetracycline in vivo and in vitro. To clarify the basis of the resistance mechanism, the effects of Tet(M) on several reactions which occur during protein synthesis were examined. The mechanism of action of Tet(M) has been clarified by two observations. The protein relieves tetracycline inhibition of factor-dependent tRNA binding and dramatically reduces the affinity of ribosomes for tetracycline when GTP is present. This reduction in drug affinity appears to be due to a large increase in the rate of tetracycline dissociation. Addition of Tet(M) to ribosome-tetracycline complexes results in displacement of bound drug. And, while Tet(M) and EF-G GTPase activities are tetracycline resistant, the two proteins differ in their sensitivities to fusidic acid, with the latter activity inhibited by the drug. Furthermore, while Tet(M) protects translation from tetracycline inhibition in a defined system, it is unable to substitute for either EF-G or elongation factor Tu.
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Tet(O) protects the bacterial ribosome from binding the antibiotic tetracycline.
“Tetracycline resistance protein Tet(O), which protects the bacterial ribosome from binding the antibiotic tetracycline, is a translational GTPase with significant similarity in both sequence and structure to the elongation factor EF-G.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [7]
Tet(M) and Tet(O) are paralogs of the translational GTPase EF-G and actively remove Tc from the ribosome in a GTP-hydrolysis-dependent fashion.
“Several of these proteins–the best-known being Tet(M) and Tet(O) – are paralogs of the translational GTPase EF-G 6 and actively remove Tc from the ribosome in a GTP-hydrolysis-dependent fashion 7,8.”
From Mechanism of tetracycline resistance by ribosomal protection protein Tet(O) (2013) · cites this paper as [7]
RPPs bind and hydrolyze GTP in a ribosome-dependent manner, and maintenance of this activity is important for in vivo activity.
“Accordingly, the RPPs bind and hydrolyze GTP in a ribosome-dependent manner (5, 6, 53), and maintenance of this activity is important for in vivo activity (11, 23).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
Tet(O) and Tet(M) can dislodge tetracycline from the ribosome.
“Tet(O) and Tet(M) can dislodge tetracycline from the ribosome (6, 54) and, in so doing, increase the apparent dissociation constant ( Kd ) of tetracycline binding to the ribosome from 5 to 30 𝛍 M.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
Tet(M) cannot substitute for the elongation factors in vivo or in vitro.
“however, Burdett (5, 6) showed that Tet(M) cannot substitute for the elongation factors in vivo or in vitro.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
Tet(O) and Tet(M) increase the apparent dissociation constant of tetracycline binding to the ribosome from 5 to 30 μM.
“Tet(O) and Tet(M) can dislodge tetracycline from the ribosome (6, 54) and, in so doing, increase the apparent dissociation constant ( Kd ) of tetracycline binding to the ribosome from 5 to 30 𝛍 M.”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
tRNA binding to the A site, which is normally inhibited by tetracycline, is protected in the presence of Tet(M).
“In accordance with the ability of Tet(O) and Tet(M) to remove tetracycline, Burdett demonstrated that tRNA binding to the A site, which is normally inhibited by tetracycline, is, in fact, protected in the presence of Tet(M) (6).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
The ability of Tet(O) and Tet(M) to dislodge tetracycline is strictly dependent on the presence of GTP.
“The ability of Tet(O) and Tet(M) to dislodge tetracycline is strictly dependent on the presence of GTP (6, 54), although there is some discrepancy concerning the role of GTP hydrolysis as a nonhydrolyzable GTP analogue was active with Tet(O) (54) but only partially active with Tet(M) (6).”
From Ribosomal Protection Proteins and Their Mechanism ofTetracyclineResistance (2003) · cites this paper as [6]
GTP hydrolysis is not strictly required to dislodge tetracycline because drug release also occurs in the presence of nonhydrolyzable GTP analogues.
“Although GTPase activity is required for multiturnover of RPPs, GTP hydrolysis is however not strictly required to dislodge tetracycline because drug release also occurs in the presence of nonhydrolyzable GTP analogues (12,13).”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [12]
TetO and TetM catalyze the release of tetracycline from the ribosome in a GTP-dependent manner.
“Accordingly, TetO and TetM catalyze the release of tetracycline from the ribosome in a GTP-dependent manner (12,13).”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [12]
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Self-citation
- Authors
- Burdett, V
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Burdett, V
- Venue
- Journal of Bacteriology
- Publisher
- American Society for Microbiology
- Published
- 1996-06
- Volume
- 178
- Issue
- 11
- Pages
- 3246-3251
- ISSN
- 0021-9193 (ISSN-L)
- 1098-5530
- PMC
- PMC178077
- OpenAlex
- W2164464764
- Cited by
- 121
- References
- 31
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 12 · 2013: 1 · 2012: 5
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Bacteriology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ai015619-18)
- National Institute of Allergy and Infectious Diseases (AI15619)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- tetracycline resistance, ribosome, elongation factor G, fusidic acid, tRNA binding, protein synthesis inhibition, antibiotic resistance mechanisms
- MeSH terms
- Anti-Bacterial Agents, Bacterial Proteins, Guanosine Triphosphate, Peptide Elongation Factors, Peptide Biosynthesis, Peptides, Ribosomes, RNA, Transfer, Tetracycline, Peptide Elongation Factor G, GTP Phosphohydrolase-Linked Elongation Factors
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