What makes an enzyme promiscuous? 2010 pdf download

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Table 1: Key Innovative Mutations. The detailed locations of the mutations listed in this table are available in Datasets S1. Table 2: Optimizing Mutations. Figure 1: Laboratory evolution method schematic and the growth trajectory of D-lyxose experiments.

A A schematic of the two-part adaptive laboratory evolution ALE ex- periments. The innovation phase involved growing cells in supplemented flasks containing the innovative substrate blue and growth-promoting supplement red. B Growth rate trajectories for duplicate experiments green and purple for the example case of D-lyxose. Population growth rates are plotted against cumulative cell divisions. Clones were isolated for whole genome se- quencing at notable growth-rate plateaus as indicated by the arrows.

Mutations gained at each plateau are highlighted beside the arrows mutations arising earlier along the trajectory persisted in later sequenced clones. Figure 2: Evaluation of enzymatic activity for the wild-type and mutated promiscuous enzyme, YihS. LC-MS was used to analyze YihS activity at saturating substrate concentrations to compare turnover rates on each substrate. Product formation was followed over time at a constant enzyme concentration.

Turnover rates were calculated using linear regression. Error bars represent standard error calculated from the linear regression analysis. A Structural mutations observed in sequencing data of Experiments Exp. The six base pair deletion observed in Exp. Scatter plot shows log2 fold change of gene expression data comparing endpoint to initial populations for Exp. Those genes that are associated with AraC transcription units are highlighted red dots for Exp. Above the plot, the transcription units are labeled green if AraC activates expression in the presence of arabinose or red if AraC represses expression of those genes.

C The proposed two pathways for metabolizing D-arabinose. The pink pathway is enabled by the optimizing mutations observed in araC. D Growth rate analysis of various innovation starting point of optimization phase and optimization endpoint of optimization phase strains with or without fucK or araB genes knocked out. Strains were grown on M9 minimal media with D-arabinose as the sole carbon source.

Figure 4: Optimization mutation analysis for the Ddeoxyribose experiment. A RNAseq expression data represented as log2 normalized expression initial population samples com- pared to the endpoint population sample for experiment Exp. Highlighted in red is rbsK associated with small mutation events and in green are genes associated with the large deletion.

Steroid Biochem. Ben-David M. Zalatan J. Ardanaz S. Lett , , — Sharma U. Amino Acids , 44 , — Masi A. FEBS J. Newton M. Stainbrook S. Protein Eng. Touw W. Nucleic Acids Res. Pundir S. Methods Mol. Sitzmann M. Kim S. Monzon A. Database Oxford , Tanabe M. Bioinformatics , Chapter 1 In: Unit1. Furnham N. Binns D. Bioinformatics , 25 , — Jehl P. Zou T. Holliday G. Gutteridge A. Gora A. Full text links Read article at publisher's site DOI : Smart citations by scite.

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Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Methods and Results. ProtMiscuity: a database of promiscuous proteins. Oxford Academic. Nicolas Palopoli. Gustavo Parisi. Email: gusparisi gmail. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract Promiscuous behaviour in proteins and enzymes remains a challenging feature to understand the structure—function relationship.

Figure 1. Open in new tab Download slide. Google Scholar Crossref. Search ADS. Recent advances in biocatalytic promiscuity: hydrolase-catalyzed reactions for nonconventional transformations.

Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways. Biological messiness vs. Also see Table 1. Table 1. Promiscuity Indices Calculated for Two 3. An important consequence of this mechanism is isoleucine 1. The expression of promiscuity under new glutamine 5. We then follow a series of ribozyme 29 in vitro evolution experiments seeking an RNA replicase, in phenylalanine 0. Substrate Promiscuity: Aminoacylation Ribozymes constants are from Illangasekare et al.

For example, selection using a phenylalanine adenylate The aminoacylating ribozymes discussed above have also substrate 1 produced ribozymes that showed little discrim- been observed to catalyze reactions using alternative ination i. Selection for aminoacylation with the RNA and the subsequent amide bond formation to coenzyme A CoA thioester 2 produced ribozymes that generate a conjugated peptide. In this section, we focus on the variety of substrates.

These ribozymes were generated over a substrate promiscuity of a self-cleaving ribozyme and how it series of selections with the ultimate goal of producing catalysts arises.

Although these ribozymes are cis-acting in vivo, they can capable of charging tRNAs with a wide variety of both natural be engineered to accept oligonucleotide substrates in trans with and non-natural substrates. The starting point of the selection multiple turnover.

The conserved nucleotides in the catalytic strand Figure 5. This substrate necessitated an altered reaction mechanism, but nevertheless, the strategy was successful, with further selection resulting in ribozymes capable of charging tRNAs without regard to amino acid side chain.

The additional substrates represent both promiscuous non-native as well as native activities. Figure 5. The catalytic strand is shown in black, and substrate is shown in green. The ribozymes even greatly reduces kcat.

The sequence dependence of the substrate, illustrates, at a identities of the sugar and base have little impact on activity, molecular level, the property of conditional substrate promiscu- despite possible hydrogen bonding interactions with these ity, in which the apparent promiscuity depends on the moieties.

However, decreasing the length of the phosphate environmental condition. The fact that two independently evolved, small changes in dissociation rate. Thus, exhibition of structurally dissimilar ribozymes have the same requirements promiscuity depends on conditions such as substrate supports the idea that substrate promiscuity is determined by concentration, pH, ionic strength, and temperature.

Condi- mechanism. In this case, evolutionary convergence on the same tional promiscuity can be the basis for cryptic genetic variation, mechanism resulted in convergence to similar promiscuity as in which an altered phenotype is uncovered in new well.

Thus, it is likely to be underappreciated in the 3. Relying on Promiscuity: Searching for an RNA literature due to observational bias, because most experimental Replicase studies tend to focus on a small set of reaction or environmental conditions.

This is an area ripe for future For those interested in the origin of life, one of the most research given the likely importance of conditional promiscuity sought-after de novo ribozyme functions is catalysis of for evolutionary innovation. The mechanism. Iso6 was recovered from a selection able to extend a primer through the incorporation of originally designed to identify ribozymes that could produce mononucleotide triphosphates.

Instead, pyrophosphate release nucleotide additions, topping out at six nucleotides added after was observed in the absence of amino acids, and the selection a six-day incubation. Selection for capping that catalytic promiscuity of the class I ligase could potentially activity using UTP instead of PPi quickly resulted in high lead to an RNA replicase. The class I ligase ribozyme and its descendants.

While there was no opposite an attached primer. One ribozyme, isolate This Mutagenized versions of the After eight more rounds of ization and selection of the template sequence strengthened selection, the best resultant ribozyme, termed the round these interactions.

However, the new nucleotides. These new mutations further increased a serious limit in the transmission of information. Reactions catalyzed by the pR1 nucleotide synthase ribozyme. Adapted with permission from ref Copyright Elsevier Ltd. Cell Press. The tC19Z ancestor of the tC19Z ribozyme to copy templates using polymerase was shown to be capable of transcribing a trinucleotide triphosphates instead of NTPs. Sequences of particular template complex. Both subunits are descended from the same concern are those with a high degree of structure that would ancestral pool, illustrating how specialized descendants need to be locally melted for ribozyme access, including originated from distinct domains of the ancestor.

Recent selections An ingenious orthogonal strategy to overcome the problem based on the RNA polymerase ribozyme focus on improving of sequence generality was developed by Joyce and coworkers, its sequence generality.

Selection for ligase activity indeed discovered structured sequences compared to the parent ribozyme. Furthermore, as with the class I ligase, these to synthesize functional RNAs up to 76 nt long and could cross-chiral ligases also possessed polymerization activity. In this case, it was hypothesized that enantiomer, which could then produce the original enan- copying via ligation of oligonucleotides could improve copying tiomer. Nevertheless, melting the template. Knowing that the RNA polymerase given the precedent of the evolutionary strides demonstrated ribozyme was originally derived from the promiscuous activity by the promiscuous class I ligase, the cross-chiral ligases of an RNA ligase, Attwater et al.

Although this work was not on mRNA into protein sequences and is conserved across all undertaken for the purpose of studying promiscuity in the domains of life. The ribosome core consists of catalytic ribozymes, the advances made with the class I ligase, spanning RNA, but farther from the catalytic center, both proteins and more than two decades of work by multiple groups, rely heavily RNA are found.

Because this associate with about 70 proteins, while in E. These results further substrates: there are 20 canonical amino acids that can be demonstrate the promiscuity of this ribozyme lineage. Catalytic Promiscuity: The Nucleotide Synthase must accommodate and catalyze. Interest- promiscuity is also observed. Indeed, an interesting case was ingly, the exit tunnel is lined primarily by RNA and lacks found in the pR1 nucleotide synthase.

These two reactions appear to have restrictions. However, the reaction with PR appears to require some slight substrate preferences. Interestingly, ribozymes selected for reactivity gene expression. Still, the degree to which ribosomes are with PRPP instead of PR did not exhibit analogous activity on capable of utilizing a wide variety of substrates, including many PR.