Cysteine-191 in aspartate aminotransferases appears to be conserved due to the lack of a neutral mutation pathway to the functional equivalent, alanine-191

Gloss, Lisa M.; Spencer, Daniel E.; Kirsch, Jack F.

doi:10.1002/(sici)1097-0134(199602)24:2<195::aid-prot6>3.0.co;2-i

Cited by 12 publications

(4 citation statements)

References 35 publications

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“…The absence of these hinge families in the 60 known species of TIM implies that there are other evolutionary criteria for which we do not select in our in vivo selection system. Alternatively, the codons for the hinges may be restricted to families 1 and 2 in nature because there is no neutral mutation pathway to access the other families (Gloss et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase

Sun

Sampson

1998

Protein Science

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We have determined the sequence requirements for a protein hinge in triosephosphate isomerase. The codons encoding the hinge at the C-terminus of the active-site lid of triosephosphate isomerase were replaced with a genetic library of all possible 8,000 amino acid combinations. The most active of these 8,000 mutants were selected using in vivo complementation of a triosephosphate isomerase deficient strain of E. coli, DF502. Approximately 3% of the mutants complement DF502 with an activity that is above 70% of wild-type activity. The sequences of these hinge mutants reveal that the solutions to the hinge flexibility problem are varied. Moreover, these preferences are sequence dependent; that is, certain pairs occur frequently. They fall into six families of similar sequences. In addition to the hinge sequences expected on the basis of phylogenetic analysis, we selected three new families of 3-amino-acid hinges: X(A/S)(L/K/ M), X(aromatic/P-branched)(L/K), and XP(S/N). The absence of these hinge families in the more than 60 known species of triosephosphate isomerase suggests that during evolution, not all of sequence space is sampled, perhaps because there is no neutral mutation pathway to access the other families.

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Section: Discussionmentioning

confidence: 99%

Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase

Sun

Sampson

1998

Protein Science

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“…The other desulfurization detected by the SeMoP algorithm corresponded to the unexpected conversion of cysteine into alanine, which could be erroneously assumed to be a mutation resulting from a single nucleotide polymorphism (SNP). However, such a mutation is highly unlikely because two nucleotides would have to be changed to convert the codon for cysteine into alanine 30, 31…”

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confidence: 99%

Reactions of Silicon Atoms with Methane and Silane in Solid Argon: A Matrix-Spectroscopic Study

2002

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A way into normality: By using [Cp*Ru] complexes with bisphosphite or bisphosphine ligands, selective hydroformylation of propene and 1‐decene to homologated normal aldehydes was accomplished with the highest levels of activity and selectivity ever reported for ruthenium catalyst systems (see scheme). The reaction mechanism was investigated using stoichiometric amounts of [Cp*Ru(Xantphos)H] and [D2]‐1‐decene.

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“…It has been proposed that Cys191 is actually a nonessential residue that has been well conserved because there is no pathway of neutral mutations to the conservative mutation Ala191, suggesting that Cys191 is a "frozen accident." 19 The nondeleterious Cys192Ser mutation was also falsely assessed as deleterious due to a medium conservation score (0.5) for the residue. The overall correct prediction accuracy for the 21 mutations in E. coli aspartate aminotransferase is 76%.…”

Section: Prediction Of Deleterious Functional Effectsmentioning

confidence: 99%

Prediction of deleterious functional effects of amino acid mutations using a library of structure‐based function descriptors

et al. 2003

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An automated, active site-focused, computational method is described for use in predicting the effects of engineered amino acid mutations on enzyme catalytic activity. The method uses structure-based function descriptors (Fuzzy Functional Forms trade mark or FFFs trade mark ) to automatically identify enzyme functional sites in proteins. Three-dimensional sequence profiles are created from the surrounding active site structure. The computationally derived active site profile is used to analyze the effect of each amino acid change by defining three key features: proximity of the change to the active site, degree of amino acid conservation at the position in related proteins, and compatibility of the change with residues observed at that position in similar proteins. The features were analyzed using a data set of individual amino acid mutations occurring at 128 residue positions in 14 different enzymes. The results show that changes at key active site residues and at highly conserved positions are likely to have deleterious effects on the catalytic activity, and that non-conservative mutations at highly conserved residues are even more likely to be deleterious. Interestingly, the study revealed that amino acid substitutions at residues in close contact with the key active site residues are not more likely to have deleterious effects than mutations more distant from the active site. Utilization of the FFF-derived structural information yields a prediction method that is accurate in 79-83% of the test cases. The success of this method across all six EC classes suggests that it can be used generally to predict the effects of mutations and nsSNPs for enzymes. Future applications of the approach include automated, large-scale identification of deleterious nsSNPs in clinical populations and in large sets of disease-associated nsSNPs, and identification of deleterious nsSNPs in drug targets and drug metabolizing enzymes.

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Cysteine-191 in aspartate aminotransferases appears to be conserved due to the lack of a neutral mutation pathway to the functional equivalent, alanine-191

Cited by 12 publications

References 35 publications

Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase

Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase

Reactions of Silicon Atoms with Methane and Silane in Solid Argon: A Matrix-Spectroscopic Study

Prediction of deleterious functional effects of amino acid mutations using a library of structure‐based function descriptors

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