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Ubiquity of aaRS Structure and Function Chemistry of Aminoacylation aaRSs: Expansion of the Genetic Code
Department of
Aminoacyl-tRNA synthetases (aaRSs) compose a family of essential enzymes that attach amino acids covalently to tRNA molecules during protein synthesis. Some aaRSs possess a hydrolytic amino acid editing function to ensure the delity of protein synthesis. In addition, aminoacylation can occur by indirect pathways that rely on mischarged tRNA intermediates and enzymes other than aaRSs. Throughout evolution, structural and functional divergence of aaRSs has yielded diverse secondary roles. Likewise, aaRS-like proteins with either sequence or structural similarities to synthetases exhibit functions that may or may not be related to aminoacylation. Many of these diverse aaRSs and aaRS-like proteins have been capitalized on by the microbial world and by medical research as targets for therapeutic agents such as antibiotics.
Aminoacyl-tRNA synthetases (aaRSs) are critical components of the translation machinery for protein synthesis in every living cell (1). Each aaRS enzyme in this family links a single amino acid covalently to one or more tRNA isoacceptors to form charged tRNAs. Identity elements within the tRNAs serve as molecular determinants or antideterminants that aid in selection by cognate aaRSs (2). Some aaRSs also have an amino acid editing mechanism to clear their mistakes (3). The canonical aaRSs and aaRS-like proteins have functionally diverged to perform many other important roles in the cell (4, 5). Their versatility and adaptability have provided unique opportunities to develop biotechnology tools and to advance medical research.
bear sequence homology to aaRS domains participate in a wide array of activities in the cell (4, 5).
Aminoacylation of tRNAs
The aaRSs catalyze the covalent attachment of an amino acid to the universal 3 -adenosine at the terminus of tRNA (1). Aminoacylation consists of a two-step reaction mechanism. First, an amino acid is activated via ATP to form an aminoacyl adenylate intermediate. Second, the amino acid is transferred to the 3 -end of tRNA, releasing AMP (Fig. 1a). Generally, amino acid activation can occur in the absence of tRNAs. However, glutamyl- (GluRS), glutaminyl- (GlnRS), arginyl- (ArgRS) and lysyl-I (LysRS-I) tRNA synthetases require tRNA as a cofactor for the activation step. Representative X-ray crystal structures have been solved for each of the 20 canonical aaRSs (Table 1). This wealth of molecular information has provided a starting point to begin to unravel diverse paradigms that govern substrate recognition, the mechanism of aminoacylation, and alternative functions. In many cases, multiple cocrystal complexes with various substrates, analogs, and inhibitors are available. Fifteen aaRS X-ray crystal structures have been solved in complexes with their cognate tRNAs. Crystallization of individual aaRS domains has also provided insight into structure-function relationships of this diverse family of enzymes.
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(a)
(b)
(c)
represents a hydrophobic amino acid). Each of the two distinct classes of aaRSs aminoacylates a set of amino acids with diverse chemical properties that would be important for protein function. Interestingly, LysRS is represented in both classes (7). Recently, two new aaRSs that activate O-phosphoserine and pyrrolysine have also been added to the Class II group (8, 9). Both classes of enzymes catalyze the common aminoacylation reaction but via different mechanisms (1). Class I and Class II aaRSs bind ATP in an extended and bent conformation, respectively (Fig. 2). In addition, class I enzymes bind the tRNA acceptor stem from the minor groove side, which orients the 2 -hydroxyl group of the A76 ribose for attachment of the amino acid (Fig. 3). In contrast, Class II aaRSs aminoacylate the 3 -hydroxyl of the terminal adenosine, because the enzyme binds to tRNA via its major groove. Class II phenylalanyl-tRNA synthetase (PheRS), which charges amino acids onto the 2 -hydroxyl group of A76 of tRNAPhe , is the only known exception to this rule. The aaRSs possess diverse polypeptide domains and insertions, in addition to their catalytic core. Likely, these domains evolved to enhance specicity and delity and, in some cases, confer other functions (4, 5). One such domain is the C-terminal anticodon-binding domain that is widely varied (1). For example, GluRS and GlnRS have highly conserved active sites within their canonical aminoacylation cores but have appended N-terminal anticodon-binding domains that are composed primarily of either -helices or -strands, respectively. In addition, common RNA-binding protein domains such as the OB-fold have been incorporated into aaRSs such as LysRS-II. In at least half of the aaRSs, an internal or appended domain confers amino acid editing activity (3).
Figure 1 Aminoacylation reaction. (a) The overall aminoacylation reaction is performed in two steps by the aaRSs. Two modes of amino acid editing can hydrolyze the mischarged tRNA product (posttransfer editing) or misactivated aminoacyl adenylate intermediate (pretransfer editing). (b) The rst step of the ATP-dependent aminoacylation reaction activates amino acid to generate an aminoacyl adenylate intermediate. (c) In the second step, the activated amino acid is transferred to the tRNA molecule and AMP is released.
The aaRSs can be divided evenly into two classes based on the architectures of their catalytic domains: the presence of specic consensus sequences and their chemical properties (6). The catalytic core of Class I aaRSs is composed of a Rossmann dinucleotide binding fold that is marked by two signature consensus sequences: KMSKS and HIGH (Fig. 2). Class II aaRSs are typically dimers or tetramers and possess a more unique catalytic core that is made up of seven antiparallel -strands anked by -helices. These enzymes have three consensus motifs (Fig. 2). Motif 1 [G XX xxP ] is at the dimer interface, whereas motif 2 [FRXE-H/RXXXFXXX(D/E)] and motif 3 [G G G (D/E)R ] are part of the active site ( 2
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Table 1 Classication of aaRSs (6, 8) and their crystal structures With amino acid/ substrate analog Individual domains
Enzyme only
With tRNA
1WKB 1WK8, 1ILE 1IYW 1QQT, 1A8H, 1WOY, 1RQG 1LI5 1BS2, 1IQ0 1NYL
2BTE, 2BYT, 1WZ2 1QU2, 1QU3, 1FFY 1IVS, 1GAX 2CT8, 2CSX
1U0B 1F7U, 1F7V 1GSG, 1GTR, 1GTS, 1QRS, 1QRT, 1QRU, 1QTQ, 1EXD, 1EUQ, 1EUY, 1ZJW 1G59, 1N77, 1N78, 2CV0, 2CV1, 2CV2
2AJG, 2AJH, 2AJI 1WNY, 1WNZ, 1UDZ, 1UE0 1WKA, 1WK9 1MEA, 1MED, 1MKH, 1PYB
1O0B, 1O0C
GluRS
1GLN
LysRS-I Ic TyrRS
1IRX 1TYA, 1TYB, 1TYC, 2CYA, 1U7D, 1U7X 1H3E, 1J1U 1TYD, 2TS1, 3TS1, 4TSI, 1WQ3, 1WQ4, 1X8X, 1H3F, 1Q11, 1JII, 1JIJ, 1JIK, 1JIL, 1VBM, 1VBN, 2CYB, 2CYC 1MAU, 1I6K, 1I6L, 1I6M, 1M83, 1YIA, 1YID, 1MAW, 1MB2, 1YI8, 1JH3, 1N3L, 1Y42, 1NTG
TrpRS
2ODR
1SRY, 2CIM
1SER 1QF6
AlaRS GlyRS ProRS 1ATI 1NJ2, 1HC7, 1NJ8, 2I4L 1H4V, 1HTT, 1QEO, 1WU7
1H4S, 1H4Q
HisRS
1YFR, 1YFS, 1YFT, 1YGB, 1RIQ 1B76, 1GGM 1NJ1, 1NJ5, 1NJ6, 1H4T, 2J3L, 2J3M, 2I4M, 2I4N, 2I4O 1KMM, 1KMN, 1ADY, 1ADJ
1EVK, 1EVL 1FYF, 2HL0, 2HL1, 2HL2, 2HKZ, 1Y2Q, 1WWT, 1TJE, 1TKE, 1TKG, 1TKY 1V4P, 1V7O 1J5W
1X59
Enzyme only
With tRNA
1EOV, 1WYD, 1ASZ, 1N9W, 1G51 1L0W, 1B8A, 1EQR 1X56 1BBW
1X54, 1X55 1BBU, 1E1O, 1E1T, 1E22, 1E24, 1LYL 1EIY 1B70, 1B7Y, 1JJC, 2ALY, 2AMC, 2IY5, 2AKW
1KRS, 1KRT
1PYS
2CXI
These aaRSs have a hydrolytic editing pathway to clear misactivated and mischarged amino acids.
aaRS-like proteins
Proteins with sequence homology to aaRSs perform diverse cellular functions (5) (Fig. 4b). Some of these proteins resulted from aaRS gene duplications and are called paralogs. Other paralogs are composed of just one domain of an aaRS that has multiple domains. Paralog examples include E. coli YadB, which resembles GluRS. YadB attaches glutamate to a queuosine base yielding an essential tRNAAsp anticodon modication. In addition, two methionyl-tRNA synthetase (MetRS)-like proteins called Arc1p and Trbp111 bind to tRNA. Although the role of Trbp111 is not understood, Arc1p aids in delivery of tRNAs to their cognate aaRSs subsequent to nuclear export. Several aaRSs possess amino acid editing domains, which hydrolytically clear mistakes in cis (3) (Table 1). Interestingly however, some archaeal and bacterial synthetases rely on paralogs of editing domains that hydrolyze mischarged products in trans (10, 11). These products include the YbaK and ProX (or PrdX), which edit Ala-tRNAPro , and AlaX that hydrolyzes mischarged Ser-tRNAAla and Gly-tRNAAla . Several aaRS-like proteins are involved in metabolic pathways (1). For example, E. coli asparagine synthase, an aspartyltRNA synthetase (AspRS)-like enzyme, catalyzes the synthesis of asparagine from aspartate and ATP. A paralog of LysRS-II, called PoxA/GenX, is important for pyruvate oxidase activity in E. coli and Salmonella typhimurium and for virulence in S. typhimurium . The E. coli biotin synthetase/repressor protein (BirA), which has a domain that resembles structurally the seryl-tRNA synthetase (SerRS) catalytic domain, activates biotin to modify posttranslationally various metabolic proteins involved in carboxylation and decarboxylation. BirA can also bind DNA and regulate its own transcription using biotin as a corepressor. A histidyl-tRNA synthetase (HisRS)-like protein from Lactococcus lactis , HisZ is involved in the allosteric activation of the phosphoribosyl-transferase reaction. 4
Binding of uncharged tRNA to a HisRS-like domain of the GCN2 kinase protein in Saccharomyces cerevisiae under starvation and stress conditions elicits a cascade of molecular events to upregulate genes for amino acid and nucleotide biosynthesis. The accessory subunit Pol of mtDNA polymerase , which shares structural homology to both the catalytic and the anticodon binding domains of glycyl-tRNA synthetase (GlyRS), increases the processivity of the catalytic subunit of DNA-Pol and was proposed to serve as a primer recognition factor.
Chemistry of Aminoacylation
Recognition of tRNAs by aaRSs
One of the most signicant features of the aminoacylation reaction is the specic recognition of a set of tRNA isoacceptors by their corresponding aaRS (2). Accurate tRNA:aaRS pairing relies on molecular identity elements that are composed of individual nucleotides, modications, base pairs, or structural motifs. Positive identity elements (or determinants) enhance the selection of a tRNA by its cognate aaRS, whereas negative identity elements (or antideterminants) prevent the formation of incorrect tRNA:aaRS pairs. These identity elements can be classied as either major or minor elements based on the level of their impact on recognition. Most identity elements are present at the two distal ends of the molecule: the acceptor stem and the triplet anticodon (Fig. 5). In the acceptor stem, the unpaired discriminator base N73 is a crucial recognition factor for most aaRSs. Also, the rst few acceptor stem base pairs often serve as determinants for many tRNAs. The structural domains of aaRSs play specic roles in the recognition of tRNAs (12). In general, the more conserved catalytic domain binds the acceptor stem during aminoacylation. As indicated, diverged domains in most aaRSs interact directly
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Figure 2 Mode of ATP binding to aaRSs. (a) Active site of GluRS enzyme bound to ATP (PDB 1 N75). The consensus sequences KISKR (KMSKS) and HVGT (HIGH) are highlighted on the protein. (b) Active site of GlyRS enzyme bound to ATP (PDB 1B76). The consensus motifs 1, 2, and 3 are highlighted on the protein. Class I and Class II aaRSs bind ATP in an extended and bent conformation, respectively. ATP is shown as dark spheres.
Figure 3 Mode of tRNA binding to aaRSs. (a) Active site of GluRS enzyme bound to ATP and tRNAGlu (PDB 1 N77). (b) Active site of AspRS enzyme bound to Asp-AMP and tRNAAsp (PDB 1 C0A). Class I and Class II enzymes bind the tRNA acceptor stem from the minor and major groove sides, respectively. This orients either the 2 -OH or 3 -OH of A76 for specic attachment of the amino acid. ATP is represented by dark spheres, and tRNA is shown as a tube.
with the tRNA anticodons to enable discrimination. The only exceptions are LeuRS, SerRS, and AlaRS, which do not require anticodon interactions for aminoacylation. SerRS and LeuRS interact, respectively, with up to four and six tRNA isoacceptors that have highly varied anticodons. In some aaRSs, accessory domains enhance recognition. Unique architectural features of tRNAs also can serve as identity elements (2). For example, the long variable loop of tRNASer interacts specically with SerRS. In addition, the tertiary G15:G48 Levitt base pair in E. coli tRNACys , and the triplet interaction in tRNAAsp , is formed between G45, and the G10:U25 pair confers identity. Occasionally, modied nucleotides can act as determinants, as in the case of E. coli tRNAIle , tRNAGlu , tRNALys , and yeast tRNAIle . All of these tRNAs contain modications in the anticodon loop. Antideterminants are dened as nucleotides that block misaminoacylation of the tRNA by a noncognate aaRS (2). A few
examples of unmodied nucleotides or base pairs that act as antideterminants include A73 in human tRNALeu that hinders aminoacylation by SerRS, U34 in yeast tRNAIle that interferes with MetRS binding, and a G3:U70 base pair in yeast tRNAAla that blocks ThrRS. In addition, lysidine 34 and m1G37 are located in the anticodon structures of E. coli tRNAIle and yeast tRNAAsp and serve as antideterminants against MetRS and ArgRS enzymes, respectively. Interestingly, tRNAs that are charged by Class I aaRSs possess antideterminants against Class II aaRSs and vice versa (2).
Reaction mechanism
The overall two-step aminoacylation reaction relies on mechanistically distinct features of the Class I and Class II enzymes (1). In the Rossmann fold of Class I aaRSs, ATP binding is stabilized by interactions with the conserved KMSKS and HIGH consensus sequences. The - and -phosphates interact with Mg2+ . The -NH3 + group of the bound amino acid 5
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(a)
tRNA Maturation Proofreading Export
DNA Binding
Cytokine-like Activity
TyrRS
Functions of aaRSs
S, rR Th
AlaRS
LeusRS, TyrRS
ValR
Transcriptional Regulation
S, H
S pR Tr
isR
S pR As
Translation Regulation
(b)
Arc1p, Trbp111 (RNA-binding)
Me tR S
s Ly
AlaRS, ProRS
SerRS
aaRSs-like proteins
Gl
AspRS
GlyRS
His RS
RS
GCN2 (Protein Kinase) YadB (tRNA modification) AlaX, ProX, YbaK (Trans-editing of mischarged tRNA)
S
Figure 4 Cellular roles of aaRSs and aaRS-like proteins. (a) Alternative functions of aaRSs. The canonical aaRSs perform diverse functions in the cell that are distinct from their primary role of aminoacylation in protein synthesis 4. (b) AaRS-like proteins. Proteins that either resemble aaRSs or are paralogs of aaRSs are widespread in nature and carry out a variety of activities 5.
is stabilized via hydrogen bonds with a conserved aspartate. Amino acid activation occurs by in-line nucleophilic displacement, where the -carboxylate oxygen of the amino acid attacks the -phosphorus atom of ATP (Fig. 1b). The exible KMSKS peptide loop forms hydrogen bonds between the conserved lysine and serine and the pyrophosphate moiety of ATP during the transition state. Cleavage of the phosphoanhydride linkage between the - and -phosphates of ATP releases PPi . In the second step, the 2 ribose hydroxyl of the tRNAs A76 attacks nucleophilically the carboxyl carbon of the aminoacyl adenylate intermediate to cleave the mixed anhydride. When amino acid is transferred to the tRNA molecule, AMP is released. In Class II aaRSs, the bound ATP molecule interacts with motifs 2 and 3 (Fig. 2). The - and -phosphates bend toward the adenine ring and are stabilized by three Mg2+ ions. The ribose of the ATP molecule adopts a 3 -endo conformation, as opposed to the 2 -endo conformation in Class I aaRSs. The amino acid side chain tends to bind by a lock-and-key mechanism, whereas its backbone interacts via an induced t. Similar to Class I 6
aaRSs, activation proceeds by an in-line nucleophilic displacement mechanism. The transition state is stabilized by interactions between the - and -phosphates and arginine residues in motifs 2 and 3, respectively. The 3 -hydroxyl of the A76 ribose nucleophilically attacks the carboxyl carbon of the aminoacyl adenylate intermediate, forming aminoacyl-tRNA and AMP. The tRNA that is charged by either of the two classes is then transferred to an elongation factor such as EF-Tu in bacteria for delivery to the ribosome.
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uR
Figure 5 ProteinRNA interactions of aaRSs. The cloverleaf secondary structure of tRNALeu folds into an L-shaped tertiary molecule. The tRNA can bind in an aminoacylation complex, where the 3 end is located in the canonical Class I or Class II core as shown in the upper right for the P. horikoshii LeuRS-tRNALeu aminoacylation complex. In aaRSs that edit, a second complex can be formed, where the 3 end interacts with a separate domain such as the connective polypeptide insertion (CP1) that contains a hydrolytic active site as shown in the lower right for the T. thermophilus LeuRS-tRNALeu editing complex. (Table (1); PDB les 1WZ2 and 2BYT).
Most aaRSs that possess an amino acid editing activity rely on a hydrolytic active site that has been integrated into their polypeptide chain. However, a few aaRSs are dependent on a mechanism where hydrolysis is carried out in trans by an independent domain (i.e., YbaK, ProX, and AlaX). MetRS and LysRS-II use the aminoacylation active site for editing and for clear mistakes by cyclizing the misactivated noncognate amino acid. Pretransfer editing has occurred both in an enzyme-based active site and in an aqueous environment via hydrolysis. The
latter, which is commonly referred to as kinetic proofreading, relies on selective release of noncognate adenylates from the enzyme. These intermediates inherently are unstable and undergo hydrolysis in solution. Most aaRSs that edit use a double-sieve mechanism. The aminoacylation active site serves as a coarse sieve and binds cognate amino acid as well as structurally related noncognate amino acids. A second hydrolytic active site acts as a ne sieve and hydrolyzes misactivated amino acids. The Class I 7
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aaRSs, LeuRS, isoleucyl- (IleRS), and valyl- (ValRS) tRNA synthetases rely on a homologous polypeptide insertion (connective polypeptide 1 or CP1 domain) for amino acid editing (Fig. 5). Class II aaRS editing domains are highly diverse. AlaRS, ThrRS, and prolyl-tRNA synthetase (ProRS) editing domains are homologous. However, the archaeal ThrRS domain is unrelated to its bacterial/eukaryotic counterpart or to the Class II homologs. Interestingly, PheRS has an editing domain that does not resemble that of any other aaRS.
solved (8). It is an 4 synthetase whose quaternary structure resembles PheRS. Pyrrolysine, the 22nd genetically encoded amino acid, is incorporated into a Methanosarcina barkeri protein in response to an in-frame UAG codon in the mRNA (9). Two different mechanisms have been proposed for the attachment of pyrrolysine to tRNAPyl . Pyrrolysyl-tRNA synthetase (PylRS) can aminoacylate tRNAPyl directly with pyrrolysine in a single step. In an indirect pathway, LysRS-I and LysRS-II, which belong to Class I and Class II aaRSs, respectively (Table 1), form a ternary complex with tRNAPyl and charge lysine onto it. The mischarged Lys-tRNAPyl would then be expected to be modied to Pyl-tRNAPyl by a mechanism that remains undened (1). Formylation of methionylated tRNAMet allows differentiation of the AUG start codon from internal AUG codons (14). MetRS aminoacylates tRNAfMet with methionine. A formyl group is linked covalently to the charged methionine via its amino moiety by the methionyl-tRNA formyltransferase enzyme, which uses N10 -formyl tetrahydrofolate as the formyl donor. This fMet-tRNAfMet molecule binds directly to the P site of the ribosome to initiate protein synthesis, as compared with the A-site to which elongator tRNAs bind.
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Table 2 Indirect pathways of aminoacylation (9, 12) Mischarged intermediate(s) Glu-tRNAGln Chemical reaction
Product Gln-tRNAGln
CH2 CH2 C O O
Asn-tRNAAsn
Asp-tRNAAsn
Archaea Bacteria
CH2 C O O
CH2 C NH2
Sec-tRNASec
Ser-tRNASec
Bacteria
1. SerRS 2. SelA
CH2 OH
CH2 Se H
Sec-tRNASec
Ser-tRNASec Sep-tRNASec
Archaea Eukaryotes
CH2 OH
CH2 OPO32
CH2 Se H
Cys-tRNACys
Sep-tRNACys
Archaea
1. SepRS 2. SepCysS
CH2 OPO32
CH2 SH
O NH2+ C O H C NH C CH2 CH2 S CH3 H
fMet-tRNAfMet
Met-tRNAfMet
Bacteria
O C O
Pyl-tRNAPyl
Lys-tRNAPyl
Archaea
ND * An
= nondiscriminating. alternative direct pathway wherein pyrrolysine is charged to tRNAPyl by pyrrolysyl-tRNA synthetase (PylRS) has also been described (9).
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proteins, can be cross-linked readily to introduce diverse chemical properties to the protein. Other novel amino acids that have been incorporated successfully into proteins via editing defective aaRSs include -aminobutyric acid by ValRS, norleucine and norvaline by IleRS and LeuRS, and unsaturated amino acids such as allylglycine, homoallylglycine, homopropargylgylcine, and 2-butynylalanine by LeuRS.
autoimmunity. More recent reports have linked aaRS defects to neurologic problems. Finally, the discovery of an impressive and growing list of aaRS alternative activities, which include roles in apoptosis, antiangiogenesis, and immunity provide new pathways to novel medicinal therapeutics.
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Kise Y, Lee SW, Park SG, Fukai S, Sengoku T, Ishii R, Yokoyama S, Kim S, Nureki O. A short peptide insertion crucial for angiostatic activity of human tryptophanyl-tRNA synthetase. Nat. Struct. Mol. Biol. 2004;11:149156.
Further Reading
Allmang C, Krol A. Selenoprotein synthesis: UGA does not end the story. Biochimie 2006;88:15611571. Champagne KS, Sissler M, Larrabee Y, Doublie S, Francklyn CS. Activation of the hetero-octameric ATP phosphoribosyl transferase through subunit interface rearrangement by a tRNA synthetase paralog. J. Biol. Chem. 2005;280:3409634104. Cusack S, Berthet-Colominas C, Hartlein M, Nassar N, Leberman R. A second class of synthetase structure revealed by X-ray anal Nature ysis of Escherichia coli seryl-tRNA synthetase at 2.5 A. 1990;347:249255. Eriani G, Delarue M, Poch O, Gangloff J, Moras D. Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs. Nature 1990;347:203206. Fan L, Sanschagrin PC, Kaguni LS, Kuhn LA. The accessory subunit of mtDNA polymerase shares structural homology with aminoacyltRNA synthetases: implications for a dual role as a primer recognition factor and processivity clamp. Proc. Natl. Acad. Sci. U.S.A. 1999;96:95279532. Finn J, Tao J. Aminoacyl-tRNA synthetases as anti-infective drug targets. In Aminoacyl-tRNA Synthetases. Ibba M, Francklyn C, Cusack S, eds. 2005. Landes Bioscience, Georgetown, TX. p. 405413. First EA. Catalysis of the tRNA aminoacylation reaction. In: AminoacyltRNA Synthetases. Ibba M, Francklyn C, Cusack S, eds. 2005. Landes Bioscience, Georgetown, TX. p. 328363. Francklyn C. tRNA synthetase-like proteins. In: Aminoacyl-tRNA Synthetases, Ibba M, Francklyn C, Cusack S, eds. 2005. Landes Bioscience, Georgetown, TX. p. 285297. Fukunaga R, Yokoyama S. Aminoacylation complex structures of leucyl-tRNA synthetase and tRNALeu reveal two modes of discriminator-base recognition. Nat. Struct. Mol. Biol. 2005; 12:915922. Geslain R, Ribas de Pouplana L. Regulation of RNA function by aminoacylation and editing ? Trends Genet. 2004; 20:604610. Hendrickson TL, de Crecy-Lagard V, Schimmel P. Incorporation of nonnatural amino acids into proteins. Annu. Rev. Biochem. 2004;73:147176. Ivakhno SS, Kornelyuk AI. Cytokine-like activities of some aminoacyltRNA synthetases and auxiliary p43 cofactor of aminoacylation reaction and their role in oncogenesis. Exp. Oncol. 2004;26:250255. K ohrer C, RajBhandary UL. Proteins with one or more unnatural amino acids. In: Aminoacyl-tRNA Synthetases. Ibba M, Francklyn C, Cusack S, eds. 2005. Landes Bioscience, Georgetown, TX. p. 353363. Kron M, H artlein M. Aminoacyl-tRNA synthetases and disease. In: Aminoacyl-tRNA Synthetases. Ibba M, Francklyn C, Cusack S, eds. 2005. Landes Bioscience, Georgetown, TX. p. 397404. Krzycki JA. The direct genetic encoding of pyrrolysine. Curr. Opin. Microbiol. 2005;8:706712. Min B, Pelaschier JT, Graham DE, Tumbula-Hansen D, S oll D. Transfer RNA-dependent amino acid biosynthesis: an essential route to asparagine formation. Proc. Natl. Acad. Sci. U.S.A. 2002;99:2678 2683.
ODonoghue P, Sethi A, Woese CR, Luthey-Schulten ZA. The evolutionary history of Cys-tRNACys formation. Proc. Natl. Acad. Sci. U.S.A. 2005;102:1900319008. Otani A, Slike BM, Dorrell MI, Hood J, Kinder K, Ewalt KL, Cheresh D, Schimmel P, Friedlander M. A fragment of human TrpRS as a potent antagonist of ocular angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 2002;99:178183. Polycarpo C, Ambrogelly A, Berube A, Winbush SM, Mc Closkey JA, Crain PF, Wood JL, S oll D. An aminoacyl-tRNA synthetase that specically activates pyrrolysine. Proc. Natl. Acad. Sci. U.S.A. 2004;101:1245012454. Polycarpo C, Ambrogelly A, Ruan B, Tumbula-Hansen D, Ataide SF, Ishitani R, Yokoyama S, Nureki O, Ibba M, S oll D. Activation of the pyrrolysine suppressor tRNA requires formation of a ternary complex with class I and class II lysyl-tRNA synthetases. Mol Cell, 2003;12:287294. Salazar JC, Ambrogelly A, Crain PF, Mc Closkey JA, S oll D. A truncated aminoacyl-tRNA synthetase modies RNA. Proc. Natl. Acad. Sci. U.S.A. 2004;101:75367541. Sauerwald A, Zhu W, Major TA, Roy H, Palioura S, Jahn D, Whitman WB, Yates JR 3rd, Ibba M, S oll D. RNA-dependent cysteine biosynthesis in archaea. Science 2005;307:19691972. Sethi A, ODonoghue P, Luthey-Schulten Z. Evolutionary proles from the QR factorization of multiple sequence alignments. Proc. Natl. Acad. Sci. U.S.A. 2005;102:40454050. Srinivasan G, James CM, Krzycki JA. Pyrrolysine encoded by UAG in Archaea: charging of a UAG-decoding specialized tRNA. Science 2002;296:14591462. Tzima E, Schimmel P. Inhibition of tumor angiogenesis by a natural fragment of a tRNA synthetase. Trends Biochem. Sci. 2006;31:710. Yuan J, Palioura S, Salazar JC, Su D, O Donoghue P, Hohn MJ, Cardoso AM, Whitman WB, S oll D. RNA-dependent conversion of phosphoserine forms selenocysteine in eukaryotes and archaea. Proc. Natl. Acad. Sci. U.S.A. 2006;103:1892318927.
See Also
Enzyme Catalysis, Chemistry of Expanding the Genetic Code Through Chemical Biology Protein Synthesis, Key Reactions of Protein-Nucleic Acid Interactions Translation: An Overview
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