Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Toward mechanistic classification of enzyme functions.

ABSTRACT: Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-grained functional descriptions than provided by the Enzyme Commission (EC) system currently in use. Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic similarities. Together, these provide a foundation for new classifications of enzyme function.

SUBMITTER: Almonacid DE

PROVIDER: S-EPMC3551611 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Toward mechanistic classification of enzyme functions.

Almonacid Daniel E DE Babbitt Patricia C PC

Current opinion in chemical biology 20110412 3

Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-gra ...[more]

PMID: 21489855

Similar Datasets

A mechanistic classification of clinical phenotypes in neuroblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-10-25 | GSE120572 | GEO

A mechanistic view of enzyme evolution.

Project description:New enzyme functions often evolve through the recruitment and optimization of latent promiscuous activities. How do mutations alter the molecular architecture of enzymes to enhance their activities? Can we infer general mechanisms that are common to most enzymes, or does each enzyme require a unique optimization process? The ability to predict the location and type of mutations necessary to enhance an enzyme's activity is critical to protein engineering and rational design. In this review, via the detailed examination of recent studies that have shed new light on the molecular changes underlying the optimization of enzyme function, we provide a mechanistic perspective of enzyme evolution. We first present a global survey of the prevalence of activity-enhancing mutations and their distribution within protein structures. We then delve into the molecular solutions that mediate functional optimization, specifically highlighting several common mechanisms that have been observed across multiple examples. As distinct protein sequences encounter different evolutionary bottlenecks, different mechanisms are likely to emerge along evolutionary trajectories toward improved function. Identifying the specific mechanism(s) that need to be improved upon, and tailoring our engineering efforts to each sequence, may considerably improve our chances to succeed in generating highly efficient catalysts in the future.

| S-EPMC7380680 | biostudies-literature

Single-Molecule Mechanistic Study of Enzyme Hysteresis.

Project description:Hysteresis is an important feature of enzyme-catalyzed reactions, as it reflects the influence of enzyme regulation in the presence of ligands such as substrates or allosteric molecules. In typical kinetic studies of enzyme activity, hysteretic behavior is observed as a "lag" or "burst" in the time course of the catalyzed reaction. These lags and bursts are due to the relatively slow transition from one state to another state of the enzyme molecule, with different states having different kinetic properties. However, it is difficult to understand the underlying mechanism of hysteresis by observing bulk reactions because the different enzyme molecules in the population behave stochastically. In this work, we studied the hysteretic behavior of mutant ?-glucuronidase (GUS) using a high-throughput single-molecule array platform and investigated the effect of thermal treatment on the hysteresis.

| S-EPMC6813718 | biostudies-literature

A mechanistic classification of clinical phenotypes in neuroblastoma.

Project description:Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

| S-EPMC7875194 | biostudies-literature

Inferring pathway activity toward precise disease classification.

Project description:The advent of microarray technology has made it possible to classify disease states based on gene expression profiles of patients. Typically, marker genes are selected by measuring the power of their expression profiles to discriminate among patients of different disease states. However, expression-based classification can be challenging in complex diseases due to factors such as cellular heterogeneity within a tissue sample and genetic heterogeneity across patients. A promising technique for coping with these challenges is to incorporate pathway information into the disease classification procedure in order to classify disease based on the activity of entire signaling pathways or protein complexes rather than on the expression levels of individual genes or proteins. We propose a new classification method based on pathway activities inferred for each patient. For each pathway, an activity level is summarized from the gene expression levels of its condition-responsive genes (CORGs), defined as the subset of genes in the pathway whose combined expression delivers optimal discriminative power for the disease phenotype. We show that classifiers using pathway activity achieve better performance than classifiers based on individual gene expression, for both simple and complex case-control studies including differentiation of perturbed from non-perturbed cells and subtyping of several different kinds of cancer. Moreover, the new method outperforms several previous approaches that use a static (i.e., non-conditional) definition of pathways. Within a pathway, the identified CORGs may facilitate the development of better diagnostic markers and the discovery of core alterations in human disease.

| S-EPMC2563693 | biostudies-literature

A mechanistic classification of clinical phenotypes in neuroblastoma (telomere maintenance cohort)

Project description:Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCN-WT TERT-WT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.

2018-10-25 | GSE120559 | GEO

Towards a mechanistic understanding of lipodystrophy and seipin functions.

Project description:CGL (Congenital generalized lipodystrophy) is a genetic disorder characterized by near complete loss of adipose tissue along with increased ectopic fat storage in other organs including liver and muscle. Of the four CGL types, BSCL2 (Berardinelli-Seip Congenital lipodystrophy type 2), resulting from mutations in the BSCL2/seipin gene, exhibits the most severe lipodystrophic phenotype with loss of both metabolic and mechanical adipose depots. The majority of Seipin mutations cause C-terminal truncations, along with a handful of point mutations. Seipin localizes to the ER and is composed of a conserved region including a luminal loop and two transmembrane domains, plus cytosolic N- and C-termini. Animal models deficient in seipin recapitulate the human lipodystrophic phenotype. Cells isolated from seipin knockout mouse models also exhibit impaired adipogenesis. Mechanistically, seipin appears to function as a scaffolding protein to bring together interacting partners essential for lipid metabolism and LD (lipid droplet) formation during adipocyte development. Moreover, cell line and genetic studies indicate that seipin functions in a cell-autonomous manner. Here we will provide a brief overview of the genetic association of the CGLs, and focus on the current understanding of differential contributions of distinct seipin domains to lipid storage and adipogenesis. We will also discuss the roles of seipin-interacting partners, including lipin 1 and 14-3-3?, in mediating seipin-dependent regulation of cellular pathways such as actin cytoskeletal remodelling.

| S-EPMC4182903 | biostudies-other

Mechanistic Enzymology of the Radical SAM Enzyme DesII.

Project description:DesII is a member of the radical SAM family of enzymes that catalyzes radical-mediated transformations of TDP-4-amino-4,6-didexoy-D-glucose as well as other sugar nucleotide diphosphates. Like nearly all radical SAM enzymes, the reactions begin with the reductive homolysis of SAM to produce a 5'-deoxyadenosyl radical which is followed by regiospecific hydrogen atom abstraction from the substrate. What happens next, however, depends on the nature of the substrate radical so produced. In the case of the biosynthetically relevant substrate, a radical-mediated deamination ensues; however, when this amino group is replaced with a hydroxyl, one instead observes dehydrogenation. The factors that govern the fate of the initially generated substrate radical as well as the mechanistic details underlying these transformations have been a key focus of research into the chemistry of DesII. This review will discuss recent discoveries pertaining to the enzymology of DesII, how it may relate to understanding other radical-mediated lyases and dehydrogenases and the working hypotheses currently being investigated regarding the mechanism of DesII catalysis.

| S-EPMC5021314 | biostudies-literature

Illuminating the mechanistic roles of enzyme conformational dynamics.

Project description:Many enzymes mold their structures to enclose substrates in their active sites such that conformational remodeling may be required during each catalytic cycle. In adenylate kinase (AK), this involves a large-amplitude rearrangement of the enzyme's lid domain. Using our method of high-resolution single-molecule FRET, we directly followed AK's domain movements on its catalytic time scale. To quantitatively measure the enzyme's entire conformational distribution, we have applied maximum entropy-based methods to remove photon-counting noise from single-molecule data. This analysis shows unambiguously that AK is capable of dynamically sampling two distinct states, which correlate well with those observed by x-ray crystallography. Unexpectedly, the equilibrium favors the closed, active-site-forming configurations even in the absence of substrates. Our experiments further showed that interaction with substrates, rather than locking the enzyme into a compact state, restricts the spatial extent of conformational fluctuations and shifts the enzyme's conformational equilibrium toward the closed form by increasing the closing rate of the lid. Integrating these microscopic dynamics into macroscopic kinetics allows us to model lid opening-coupled product release as the enzyme's rate-limiting step.

| S-EPMC2084295 | biostudies-literature

A mechanistic classification of clinical phenotypes in neuroblastoma (TERT expression threshold cohort)

Project description:Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCNWT TERTWT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.

2018-10-25 | GSE120568 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data