Quality control by<i>trans</i>-editing factor prevents global mistranslation of non-protein amino acid α-aminobutyrate

Bacusmo, Jo Marie; Kuzmishin, Alexandra B.; Cantara, William A.; Suga, Hiroaki; Musier‐Forsyth, Karin

doi:10.1080/15476286.2017.1353846

Cited by 14 publications

(10 citation statements)

References 71 publications

(147 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, trans-acting hydrolytic editing proteins have been found to resolve particularly difficult discrimination problems arising from the misacylation of near-cognate primary metabolites. For example, AlaX-like proteins can hydrolyze Ser-tRNA Ala , while members of the INS superfamily have been shown to act on various substrates including misacylated cysteinyl-, threonyl-, seryl-, and aminobutyryl-tRNA (25,26,32,46). In contrast to these housekeeping functions, FthB participates in mediating secondary metabolism, a finding that gives rise to the possibility that related proteins have been adapted to prevent mistranslation and enable the usage of specialized amino acids for natural product biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya

McMurry

Chang

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Fluorine is an element with unusual properties that has found significant utility in the design of synthetic small molecules, ranging from therapeutics to materials. In contrast, only a few fluorinated compounds made by living organisms have been found to date, most of which derive from the fluoroacetate/fluorothreonine biosynthetic pathway first discovered in While fluoroacetate has long been known to act as an inhibitor of the tricarboxylic acid cycle, the fate of the amino acid fluorothreonine is still not well understood. Here, we show that fluorothreonine can be misincorporated into protein in place of the proteinogenic amino acid threonine. We have identified two conserved proteins from the organofluorine biosynthetic locus, FthB and FthC, that are involved in managing fluorothreonine toxicity. Using a combination of biochemical, genetic, physiological, and proteomic studies, we show that FthB is a-acting transfer RNA (tRNA) editing protein, which hydrolyzes fluorothreonyl-tRNA 670-fold more efficiently than threonyl-RNA, and assign a role to FthC in fluorothreonine transport. While -acting tRNA editing proteins have been found to counteract the misacylation of tRNA with commonly occurring near-cognate amino acids, their role has yet to be described in the context of secondary metabolism. In this regard, the recruitment of tRNA editing proteins to biosynthetic clusters may have enabled the evolution of pathways to produce specialized amino acids, thereby increasing the diversity of natural product structure while also attenuating the risk of mistranslation that would ensue.

show abstract

Section: Resultsmentioning

confidence: 99%

Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya

McMurry

Chang

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Moreover, whether such a tRNA-based discriminatory code exists for other standalone proofreading modules such as AlaXs, YbaK and ProXp-ala remains to be probed. Interestingly, such an acceptor stem based tRNA determinants has been shown to exist for other standalone proofreading modules also such as AlaXs, YbaK and ProXp-ala ( Bacusmo et al, 2017 ; Beebe et al, 2008 ; Das et al, 2014 ; Vargas-Rodriguez and Musier-Forsyth, 2013 ). These findings also suggest that bacterial DTD and A/G73-containing tRNA Gly or eukaryotic DTD and U/C73-containing tRNA Gly are likely to be incompatible.…”

Section: Discussionmentioning

confidence: 99%

A discriminator code–based DTD surveillance ensures faithful glycine delivery for protein biosynthesis in bacteria

Kuncha

Suma

Pawar

et al. 2018

eLife

View full text Add to dashboard Cite

D-aminoacyl-tRNA deacylase (DTD) acts on achiral glycine, in addition to D-amino acids, attached to tRNA. We have recently shown that this activity enables DTD to clear non-cognate Gly-tRNAAla with 1000-fold higher efficiency than its activity on Gly-tRNAGly, indicating tRNA-based modulation of DTD (Pawar et al., 2017). Here, we show that tRNA’s discriminator base predominantly accounts for this activity difference and is the key to selection by DTD. Accordingly, the uracil discriminator base, serving as a negative determinant, prevents Gly-tRNAGly misediting by DTD and this protection is augmented by EF-Tu. Intriguingly, eukaryotic DTD has inverted discriminator base specificity and uses only G3•U70 for tRNAGly/Ala discrimination. Moreover, DTD prevents alanine-to-glycine misincorporation in proteins rather than only recycling mischarged tRNAAla. Overall, the study reveals the unique co-evolution of DTD and discriminator base, and suggests DTD’s strong selection pressure on bacterial tRNAGlys to retain a pyrimidine discriminator code.

show abstract

“…Also, in many archaeal ThrRSs the N-terminal editing domain is replaced by a module homologous to the DTD fold. Interestingly, ProXp factors with relaxed specificity recognizing multiple mischarged tRNAs, even with nonproteinogenic amino acids, were recently discovered (Bacusmo et al, 2018). 4.…”

Section: Errors and Error Preventionmentioning

confidence: 99%

Transfer RNA Recognition and Aminoacylation by Synthetases

Giegé

Eriani

2021

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Fidelity of transfer ribonucleic acid (tRNA) charging by amino acids ensures correct translation of the genetic code into proteins. Charging is catalysed by a set of enzymes known as aminoacyl-tRNA synthetases. Owing to the degeneracy of the genetic code, some of the different tRNAs have the same amino acid attached to them. Specificity of charging obeys universal rules and is ensured by positive elements, the identity determinants unique to each tRNA and responsible for its recognition by the cognate synthetase, and negative elements, the antideterminants that prevent false recognitions. To fulfil the aminoacylation specificity and prevent noncognate aminoacyl-tRNA delivery to the ribosome, some synthetases also mediate proofreading reactions that increase fidelity of the tRNA charging. In such reactions, misactivated amino acids or mischarged tRNAs are checked in specific sites and noncognate products are hydrolysed. However, mischarging is beneficial under certain stress circumstances or when catalysed by nondiscriminatory synthetases, and represents a driving force in evolution. Key Concepts:•Translational expression of the genetic code refers to aminoacyl-tRNA-and ribosomedependent decoding of genes into proteins, a process highly dependent on fidelity of tRNA aminoacylation by synthetases.•The rules that account for the aminoacylation identity of tRNAs are referred to as the second genetic code.•The RNA operational code is encoded in the acceptor stem of tRNA and is crucial for recognition by aminoacyl-tRNA synthetases and specific aminoacylation.•Allostery in tRNA-synthetase systems concerns long-range transfer of chemical information (up to 75 Å) to the synthetase catalytic site (through the body of tRNA and/or synthetase) triggered by contacts of tRNA identity determinants with the synthetase.•Engineering the identity of tRNA-synthetase systems allows reprogramming the genetic code.

show abstract

Quality control bytrans-editing factor prevents global mistranslation of non-protein amino acid α-aminobutyrate

Cited by 14 publications

References 71 publications

Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya

Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer Streptomyces cattleya

A discriminator code–based DTD surveillance ensures faithful glycine delivery for protein biosynthesis in bacteria

Transfer RNA Recognition and Aminoacylation by Synthetases

Contact Info

Product

Resources

About