scholarly journals Harnessing natural diversity to identify key amino acid residues in prolidase

2018 ◽  
Author(s):  
Hanna Marie Schilbert ◽  
Vanessa Pellegrinelli ◽  
Sergio Rodriguez-Cuenca ◽  
Antonio Vidal-Puig ◽  
Boas Pucker
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
3D Structure ◽  
Single Amino Acid ◽  
Nucleotide Polymorphisms ◽  
Prolidase Deficiency ◽  
Pathogenic Potential ◽  
Conserved Residues ◽  
Amino Acid Mutations ◽  
Living Organisms

Prolidase (PEPD) catalyses the cleavage of dipeptides with high affinity for proline at the C-terminal end. This function is required in almost all living organisms. In order to detect strongly conserved residues in PEPD, we analysed PEPD orthologous sequences identified in data sets of animals, plants, fungi, archaea, and bacteria. Due to conservation over very long evolutionary time, conserved residues are likely to be of functional relevance. Single amino acid mutations inPEPDcause a disorder called prolidase deficiency and are associated with various cancer types. We provide new insights into 15 additional residues with putative roles in prolidase deficiency and cancer. Moreover, our results confirm previous reports identifying five residues involved in the binding of metal cofactors as highly conserved and enable the classification of several non-synonymous single nucleotide polymorphisms as likely pathogenic and seven as putative polymorphisms. Moreover, more than 50 novel conserved residues across species were identified. Conservation degree per residue across the animal kingdom were mapped to the human PEPD 3D structure revealing the strongest conservation close to the active site accompanied with a higher functional implication and pathogenic potential, validating the importance of a characteristic active site fold for prolidase identity.

scholarly journals Direct coupling analysis improves the identification of beneficial amino acid mutations for the functional thermostabilization of a delicate decarboxylase

2019 ◽  
Vol 400 (11) ◽  
pp. 1519-1527 ◽  
Author(s):  
Martin Peng ◽  
Manfred Maier ◽  
Jan Esch ◽  
Alexander Schug ◽  
Kersten S. Rabe
Keyword(s):  
Amino Acid ◽  
Sequence Data ◽  
3D Structure ◽  
Three Dimensional ◽  
Computational Method ◽  
Single Amino Acid ◽  
Thiamine Pyrophosphate ◽  
Physical Parameters ◽  
Computer Based ◽  
Amino Acid Mutations

Abstract The optimization of enzyme properties for specific reaction conditions enables their tailored use in biotechnology. Predictions using established computer-based methods, however, remain challenging, especially regarding physical parameters such as thermostability without concurrent loss of activity. Employing established computational methods such as energy calculations using FoldX can lead to the identification of beneficial single amino acid substitutions for the thermostabilization of enzymes. However, these methods require a three-dimensional (3D)-structure of the enzyme. In contrast, coevolutionary analysis is a computational method, which is solely based on sequence data. To enable a comparison, we employed coevolutionary analysis together with structure-based approaches to identify mutations, which stabilize an enzyme while retaining its activity. As an example, we used the delicate dimeric, thiamine pyrophosphate dependent enzyme ketoisovalerate decarboxylase (Kivd) and experimentally determined its stability represented by a T50 value indicating the temperature where 50% of enzymatic activity remained after incubation for 10 min. Coevolutionary analysis suggested 12 beneficial mutations, which were not identified by previously established methods, out of which four mutations led to a functional Kivd with an increased T50 value of up to 3.9°C.

scholarly journals Genetic Variation and Evolution of the 2019 Novel Coronavirus

2021 ◽  
pp. 1-13
Author(s):  
Salvatore Dimonte ◽  
Muhammed Babakir-Mina ◽  
Taib Hama-Soor ◽  
Salar Ali
Keyword(s):  
Amino Acid ◽  
Receptor Binding ◽  
Rapid Evolution ◽  
Single Amino Acid ◽  
Angiotensin Converting Enzyme 2 ◽  
New Type ◽  
Amino Acid Mutations ◽  
Host Infection ◽  
Human Coronaviruses ◽  
Novel Coronavirus

<b><i>Introduction:</i></b> SARS-CoV-2 is a new type of coronavirus causing a pandemic severe acute respiratory syndrome (SARS-2). Coronaviruses are very diverting genetically and mutate so often periodically. The natural selection of viral mutations may cause host infection selectivity and infectivity. <b><i>Methods:</i></b> This study was aimed to indicate the diversity between human and animal coronaviruses through finding the rate of mutation in each of the spike, nucleocapsid, envelope, and membrane proteins. <b><i>Results:</i></b> The mutation rate is abundant in all 4 structural proteins. The most number of statistically significant amino acid mutations were found in spike receptor-binding domain (RBD) which may be because it is responsible for a corresponding receptor binding in a broad range of hosts and host selectivity to infect. Among 17 previously known amino acids which are important for binding of spike to angiotensin-converting enzyme 2 (ACE2) receptor, all of them are conservative among human coronaviruses, but only 3 of them significantly are mutated in animal coronaviruses. A single amino acid aspartate-454, that causes dissociation of the RBD of the spike and ACE2, and F486 which gives the strength of binding with ACE2 remain intact in all coronaviruses. <b><i>Discussion/Conclusion:</i></b> Observations of this study provided evidence of the genetic diversity and rapid evolution of SARS-CoV-2 as well as other human and animal coronaviruses.

Structural assessment of single amino acid mutations: application to TP53 function

2006 ◽  
Vol 27 (9) ◽  
pp. 926-937 ◽  
Author(s):  
Yum L. Yip ◽  
Vincent Zoete ◽  
Holger Scheib ◽  
Olivier Michielin
Keyword(s):  
Amino Acid ◽  
Single Amino Acid ◽  
Structural Assessment ◽  
Amino Acid Mutations

scholarly journals Molecular epidemiologic characteristics of hemagglutinin from five waves of avian influenza A (H7N9) virus infection, from 2013 to 2017, in Zhejiang Province, China

2021 ◽  
Author(s):  
Yi Sun ◽  
Haiyan Mao ◽  
Xiuyu Lou ◽  
Xinying Wang ◽  
Yin Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Influenza A ◽  
Zhejiang Province ◽  
Personal Genome ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Amino Acid Mutations ◽  
Influenza Outbreaks ◽  
Epidemiological Characteristics ◽  
The Waves

AbstractThere have been five waves of influenza A (H7N9) epidemics in Zhejiang Province between 2013 and 2017. Although the epidemiological characteristics of the five waves have been reported, the molecular genetics aspects, including the phylogeny, evolution, and mutation of hemagglutinin (HA), have not been systematically investigated. A total of 154 H7N9 samples from Zhejiang Province were collected between 2013 and 2017 and sequenced using an Ion Torrent Personal Genome Machine. The starting dates of the waves were 16 March 2013, 1 July 2013, 1 July 2014, 1 July 2015, and 1 July 2016. Single-nucleotide polymorphisms (SNPs) and amino acid mutations were counted after the HA sequences were aligned. The evolution of H7N9 matched the temporal order of the five waves, among which wave 3 played an important role. The 55 SNPs and 14 amino acid mutations with high frequency identified among the five waves revealed the dynamic occurrence of mutation in the process of viral dissemination. Wave 3 contributed greatly to the subsequent epidemic of waves 4 and 5 of H7N9. Compared with wave 1, wave 5 was characterized by more mutations, including A143V and R148K, two mutations that have been reported to weaken the immune response. In addition, some amino acid mutations were observed in wave 5 that led to more lineages. It is necessary to strengthen the surveillance of subsequent H7N9 influenza outbreaks.

scholarly journals Mutations in Plasmodium falciparumCytochrome b That Are Associated with Atovaquone Resistance Are Located at a Putative Drug-Binding Site

2000 ◽  
Vol 44 (8) ◽  
pp. 2100-2108 ◽  
Author(s):  
Michael Korsinczky ◽  
Nanhua Chen ◽  
Barbara Kotecka ◽  
Allan Saul ◽  
Karl Rieckmann ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Point Mutations ◽  
Drug Binding ◽  
Single Amino Acid ◽  
Malaria Parasites ◽  
Drug Binding Site ◽  
Sole Agent ◽  
Amino Acid Mutations

ABSTRACT Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc 1 (CYTbc 1) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYTb.

Optimization of Fe3O4 nanozyme activity via single amino acid modification mimicking an enzyme active site

2017 ◽  
Vol 53 (2) ◽  
pp. 424-427 ◽  
Author(s):  
Kelong Fan ◽  
Hui Wang ◽  
Juqun Xi ◽  
Qi Liu ◽  
Xiangqin Meng ◽  
...  
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
Catalytic Efficiency ◽  
Single Amino Acid ◽  
Acid Modification ◽  
Histidine Modification ◽  
Enzyme Active Site ◽  
Amino Acid Modification

Histidine modification effectively improved the affinity of Fe3O4 nanozyme to H2O2, enhancing its catalytic efficiency by mimicking peroxidase active site.

Single amino acid mutations ofMedicagoglycosyltransferase UGT85H2 enhance activity and impart reversibility

FEBS Letters ◽  
2009 ◽  
Vol 583 (12) ◽  
pp. 2131-2135 ◽  
Author(s):  
Luzia V. Modolo ◽  
Luis L. Escamilla-Treviño ◽  
Richard A. Dixon ◽  
Xiaoqiang Wang
Keyword(s):  
Amino Acid ◽  
Single Amino Acid ◽  
Amino Acid Mutations ◽  
Enhance Activity

scholarly journals Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia

2008 ◽  
Vol 141 (6) ◽  
pp. 808-813 ◽  
Author(s):  
Marloes R. Tijssen ◽  
Franca di Summa ◽  
Sonja van den Oudenrijn ◽  
Jaap Jan Zwaginga ◽  
C. Ellen van der Schoot ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Amino Acid ◽  
Single Amino Acid ◽  
Thrombopoietin Receptor ◽  
Amino Acid Mutations

scholarly journals PREMONITION - Preprocessing motifs in protein structures for search acceleration

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 217 ◽  
Author(s):  
Sandeep Chakraborty ◽  
Basuthkar J. Rao ◽  
Bjarni Asgeirsson ◽  
Ravindra Venkatramani ◽  
Abhaya M. Dandekar
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Active Site ◽  
Active Sites ◽  
Protein Structures ◽  
3D Structure ◽  
Search Space ◽  
Computational Method ◽  
Computational Time ◽  
Active Site Residues

The remarkable diversity in biological systems is rooted in the ability of the twenty naturally occurring amino acids to perform multifarious catalytic functions by creating unique structural scaffolds known as the active site. Finding such structrual motifs within the protein structure is a key aspect of many computational methods. The algorithm for obtaining combinations of motifs of a certain length, although polynomial in complexity, runs in non-trivial computer time. Also, the search space expands considerably if stereochemically equivalent residues are allowed to replace an amino acid in the motif. In the present work, we propose a method to precompile all possible motifs comprising of a set (n=4 in this case) of predefined amino acid residues from a protein structure that occur within a specified distance (R) of each other (PREMONITION). PREMONITION rolls a sphere of radius R along the protein fold centered at the C atom of each residue, and all possible motifs are extracted within this sphere. The number of residues that can occur within a sphere centered around a residue is bounded by physical constraints, thus setting an upper limit on the processing times. After such a pre-compilation step, the computational time required for querying a protein structure with multiple motifs is considerably reduced. Previously, we had proposed a computational method to estimate the promiscuity of proteins with known active site residues and 3D structure using a database of known active sites in proteins (CSA) by querying each protein with the active site motif of every other residue. The runtimes for such a comparison is reduced from days to hours using the PREMONITION methodology.

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