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The natural history of biocatalytic mechanisms.

ABSTRACT: Phylogenomic analysis of the occurrence and abundance of protein domains in proteomes has recently showed that the ?/? architecture is probably the oldest fold design. This holds important implications for the origins of biochemistry. Here we explore structure-function relationships addressing the use of chemical mechanisms by ancestral enzymes. We test the hypothesis that the oldest folds used the most mechanisms. We start by tracing biocatalytic mechanisms operating in metabolic enzymes along a phylogenetic timeline of the first appearance of homologous superfamilies of protein domain structures from CATH. A total of 335 enzyme reactions were retrieved from MACiE and were mapped over fold age. We define a mechanistic step type as one of the 51 mechanistic annotations given in MACiE, and each step of each of the 335 mechanisms was described using one or more of these annotations. We find that the first two folds, the P-loop containing nucleotide triphosphate hydrolase and the NAD(P)-binding Rossmann-like homologous superfamilies, were ?/? architectures responsible for introducing 35% (18/51) of the known mechanistic step types. We find that these two oldest structures in the phylogenomic analysis of protein domains introduced many mechanistic step types that were later combinatorially spread in catalytic history. The most common mechanistic step types included fundamental building blocks of enzyme chemistry: "Proton transfer," "Bimolecular nucleophilic addition," "Bimolecular nucleophilic substitution," and "Unimolecular elimination by the conjugate base." They were associated with the most ancestral fold structure typical of P-loop containing nucleotide triphosphate hydrolases. Over half of the mechanistic step types were introduced in the evolutionary timeline before the appearance of structures specific to diversified organisms, during a period of architectural diversification. The other half unfolded gradually after organismal diversification and during a period that spanned ?2 billion years of evolutionary history.

SUBMITTER: Nath N

PROVIDER: S-EPMC4038463 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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The natural history of biocatalytic mechanisms.

Nath Neetika N Mitchell John B O JB Caetano-Anollés Gustavo G

PLoS computational biology 20140529 5

Phylogenomic analysis of the occurrence and abundance of protein domains in proteomes has recently showed that the α/β architecture is probably the oldest fold design. This holds important implications for the origins of biochemistry. Here we explore structure-function relationships addressing the use of chemical mechanisms by ancestral enzymes. We test the hypothesis that the oldest folds used the most mechanisms. We start by tracing biocatalytic mechanisms operating in metabolic enzymes along ...[more]

PMID: 24874434

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Project description:Intravascular lymphomatosis (IVL) is a rare and clinically devastating form of extranodal B-cell non-Hodgkin's lymphoma. We performed a comprehensive analysis of the literature on IVL's published between 1959 and 2011 and evaluated the natural history as well as identified prognostic and predictive factors in patients. Nonparametric two-tailed Mann-Whitney U-test and Mantel-Cox log rank test were used to evaluate the survival intervals and prognostic factors. Multivariate analysis of variance (MANOVA) and chi-squared statistics were carried out to examine treatment-related predictive factors. Of the 740 patients with IVL, 651 (88%) had a diagnosis of B-cell lymphoma, 45 (6%) with T-cell lymphoma, and 12 patients (2%) with NK cell lymphoma. Central nervous system (CNS) IVL had the highest proportion of postmortem diagnosis, 250 (60%) compared to 21 (8%) of skin, 28 (11%) of bone marrow (BM) and spleen, and 17 (7%) of lung IVL's. Age <70 years (P = 0.0073), non-CNS site of initial diagnosis (P = 0.0014), lactate dehydrogenase (LDH) <700 (P = 0.0112), and rituximab treatment (P < 0.0001) were favorable prognostic factors. Gender, ethnicity, hemoglobin, BM biopsy, and the type of imaging studies used were not significant. Rituximab and doxorubicin treatment worked significantly better in patients with age >71 and LDH >577 compared to nonrituximab, nondoxorubicin regimens (MANOVA 2 degrees of freedom, P = 0.0345), with a median time from treatment to death of 20.0 (95% confidence interval [CI] 14.0-N/A, n = 14) months versus 2.0 (95%CI 0.5-N/A, n = 5) (?(2) = 4.7, P = 0.0304). Patients with CNS IVL relapsed primarily in the CNS (88%) while same-organ relapse occurred less frequently in skin (23%), BM and spleen (50%) and lung (20%) IVL's. Our results indicate that IVL is primarily a disease of B-lymphoma cells. Timely diagnosis and treatment with rituximab-based chemotherapy improve patient survival. The pattern of recurrence is different between CNS IVL and IVL's in other organs.

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The natural history of biocatalytic mechanisms.

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The natural history of biocatalytic mechanisms.

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