Systematic Analysis of Large Enzyme Families: Identification of Specificity‐ and Selectivity‐Determining Hotspots

Pleiss, Jürgen

doi:10.1002/cctc.201300950

Cited by 23 publications

(20 citation statements)

References 40 publications

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“…However, global sequence identity might be indicative, but not sufficient for functional annotation . Therefore, information on the protein structure has been suggested to improve the quality of sequence alignments, for the prediction of substrate specificities, and for the design of enzymes . As a consequence, large‐scale structural genomics projects sought to populate protein structure space …”

Section: Discussionmentioning

confidence: 99%

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

et al. 2019

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Thiamine diphosphate‐dependent decarboxylases catalyze both cleavage and formation of CC bonds in various reactions, which have been assigned to different homologous sequence families. This work compares 53 ThDP‐dependent decarboxylases with known crystal structures. Both sequence and structural information were analyzed synergistically and data were analyzed for global and local properties by means of statistical approaches (principle component analysis and principal coordinate analysis) enabling complexity reduction. The different results obtained both locally and globally, that is, individual positions compared with the overall protein sequence or structure, revealed challenges in the assignment of separated homologous families. The methods applied herein support the comparison of enzyme families and the identification of functionally relevant positions. The findings for the family of ThDP‐dependent decarboxylases underline that global sequence identity alone is not sufficient to distinguish enzyme function. Instead, local sequence similarity, defined by comparisons of structurally equivalent positions, allows for a better navigation within several groups of homologous enzymes. The differentiation between homologous sequences is further enhanced by taking structural information into account, such as BioGPS analysis of the active site properties or pairwise structural superimpositions. The methods applied herein are expected to be transferrable to other enzyme families, to facilitate family assignments for homologous protein sequences.

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Section: Discussionmentioning

confidence: 99%

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

et al. 2019

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“…Detailed results from biocatalytic experiments are invaluable in many fields of research, including protein design, [1][2][3][4] synthetic biochemical pathwayc onstruction, [58] reactiono ptimization, and process design.T herefore, guidelines for reporting enzymatic [34] and biocatalytic data [35] have been proposed. Guidelines have also been proposed in other fields, such as systems biology [59] and crystallization.…”

Section: Representation Of Biochemical Datamentioning

confidence: 99%

“…[3] Thus, data on protein sequence, protein structure, and the effects of mutationso nb iochemical properties are the preciousr aw materialf or successfulp rotein design. [4] Comprehensiveo nline repositories such as the National Center for Biotechnology Information (NCBI)G enBank, [5] UniProt, [6] DNA Data Bank of Japan (DDBJ), [7] and Protein Data Bank (PDB) [8] enable systematic analyses of sequences and structures of biocata-lysts. The results from experimental mutational studies are reportedi ns cientific papers, and can be accessed from repositories such as NCBI PubMed, [9] Web of Science, [10] Google Scholar, [11] or SciFinder.…”

Section: Introductionmentioning

confidence: 99%

BioCatNet: A Database System for the Integration of Enzyme Sequences and Biocatalytic Experiments

et al. 2016

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The development of novel enzymes for biocatalytic processes requires knowledge on substrate profile and selectivity; this can be derived from databases and from publications. Often, these sources lack time-course data for the substrate or product, and an unambiguous link between experiment and enzyme sequence. The lack of integrated, original data hampers the comprehensive analysis of enzyme kinetics and the evaluation of sequence-function relationships. In order to accelerate enzyme engineering, BioCatNet integrates protein sequence, protein structure, and experimental data for a given enzyme family. BioCatNet explicitly assigns the enzyme sequence to the experimental data, which consists of information on reaction conditions and time-course data. BioCatNet facilitates the consistent documentation of reaction conditions, the archiving of time-course data, and the efficient exchange of experimental data among collaborators. Data integration is demonstrated for three case studies by using the TEED (Thiamine diphosphate-dependent Enzymes Engineering Database).

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“…Pleiss et al have used MD simulations methods to rational design the P450 BM-3 active site and identify potential mutation sites (Pleiss, 2014). They have used amino acid sequences and tridimensional structures of active sites in several cytochromes P450 to obtain sequencestructure-function relationships.…”

Section: Aided Rational Design Of the Active Sitementioning

confidence: 99%

Structure, dynamics, and function of the monooxygenase P450 BM-3: insights from computer simulations studies

Roccatano

2015

J. Phys.: Condens. Matter

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Abstract. The monooxygenase P450 BM-3 is a NADPH-dependent fatty acid hydroxylase enzyme isolated from soil bacterium Bacillus megaterium. As a pivotal member of cytochrome P450 superfamily, it has been intensely studied for the comprehension of structure-dynamics-function relationships in this class of enzymes. In addition, due to its peculiar properties, it is also a promising enzyme for biochemical and biomedical applications. However, despite the efforts, the full understanding of the enzyme structure and dynamics is not yet achieved. Computational studies, in particular molecular dynamics (MD) simulations, are given important contributes to this endeavor by providing new insights at atomic level on the correlations between structure, dynamics and function of the protein. This topical review will summarize computational studies based on MD simulations of the cytochrome P450 BM-3 and it will give an outlook on future directions. 2

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Systematic Analysis of Large Enzyme Families: Identification of Specificity‐ and Selectivity‐Determining Hotspots

Cited by 23 publications

References 40 publications

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

Navigating within thiamine diphosphate‐dependent decarboxylases: Sequences, structures, functional positions, and binding sites

BioCatNet: A Database System for the Integration of Enzyme Sequences and Biocatalytic Experiments

Structure, dynamics, and function of the monooxygenase P450 BM-3: insights from computer simulations studies

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