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PubMed2004

Cytochrome p-450-mediated differential oxidative modification of proteins: albumin, apolipoprotein E, and CYP2E1 as targets.

Although many studies established a role of cytochrome P-450s in metabolism of xenobiotics, few studies evaluating the ability of cytochrome P-450s to oxidize proteins have been reported. The ability of cytochrome P-450s to induce oxidative modification of albumin, apolipoprotein E, and CYP2E1 protein was investigated. Microsomal cytochrome P-450s induced production of reactive radical species, leading to differential modification of the proteins. Albumin remained unmodified, and CYP2E1 protein was degraded, whereas recombinant and endogenous apolipoprotein E was aggregated. The modification of apolipoprotein E was isoform independent. Cytochrome P-450 inhibitors or antioxidants inhibited the production of reactive radical species and protein modification. These results demonstrate that response of each protein to cytochrome P-450-mediated oxidative attack is different, and cytochrome P-450s can induce apolipoprotein E aggregation, a process that might be relevant to accumulation of altered protein in various abnormal conditions. In view of the ubiquitous expression of cytochrome P-450s, the present results may have important toxicological implications.

Albumins↗

PubMed2000

The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway.

Autophagy and the Cvt pathway are examples of nonclassical vesicular transport from the cytoplasm to the vacuole via double-membrane vesicles. Apg8/Aut7, which plays an important role in the formation of such vesicles, tends to bind to membranes in spite of its hydrophilic nature. We show here that the nature of the association of Apg8 with membranes changes depending on a series of modifications of the protein itself. First, the carboxy-terminal Arg residue of newly synthesized Apg8 is removed by Apg4/Aut2, a novel cysteine protease, and a Gly residue becomes the carboxy-terminal residue of the protein that is now designated Apg8FG. Subsequently, Apg8FG forms a conjugate with an unidentified molecule "X" and thereby binds tightly to membranes. This modification requires the carboxy-terminal Gly residue of Apg8FG and Apg7, a ubiquitin E1-like enzyme. Finally, the adduct Apg8FG-X is reversed to soluble or loosely membrane-bound Apg8FG by cleavage by Apg4. The mode of action of Apg4, which cleaves both newly synthesized Apg8 and modified Apg8FG, resembles that of deubiquitinating enzymes. A reaction similar to ubiquitination is probably involved in the second modification. The reversible modification of Apg8 appears to be coupled to the membrane dynamics of autophagy and the Cvt pathway.

Amino Acid Sequence↗

PubMed1992

Grayanotoxin-I-modified eel electroplax sodium channels. Correlation with batrachotoxin and veratridine modifications.

To probe the structure-function relationships of voltage-dependent sodium channels, we have been examining the mechanisms of channel modification by batrachotoxin (BTX), veratridine (VTD), and grayanotoxin-I (GTX), investigating the unifying mechanisms that underlie the diverse modifications of this class of neurotoxins. In this paper, highly purified sodium channel polypeptides from the electric organ of the electric eel were incorporated into planar lipid bilayers in the presence of GTX for comparison with our previous studies of BTX (Recio-Pinto, E., D. S. Duch, S. R. Levinson, and B. W. Urban. 1987. J. Gen. Physiol. 90:375-395) and VTD (Duch, D. S., E. Recio-Pinto, C. Frenkel, S. R. Levinson, and B. W. Urban. 1989. J. Gen. Physiol. 94:813-831) modifications. GTX-modified channels had a single channel conductance of 16 pS. An additional large GTX-modified open state (40-55 pS) was found which occurred in bursts correlated with channel openings and closings. Two voltage-dependent processes controlling the open time of these modified channels were characterized: (a) a concentration-dependent removal of inactivation analogous to VTD-modified channels, and (b) activation gating similar to BTX-modified channels, but occurring at more hyperpolarized potentials. The voltage dependence of removal of inactivation correlated with parallel voltage-dependent changes in the estimated K1/2 of VTD and GTX modifications. Ranking either the single channel conductances or the depolarization required for 50% activation, the same sequence is obtained: unmodified > BTX > GTX > VTD. The efficacy of the toxins as activators follows the same ranking (Catterall, W. A. 1977. J. Biol. Chem. 252:8669-8676).

Animals↗

PubMed1993

Modification of cardiac sodium channels by carboxyl reagents. Trimethyloxonium and water-soluble carbodiimide.

In TTX-sensitive nerve and skeletal muscle Na+ channels, selective modification of external carboxyl groups with trimethyloxonium (TMO) or water-soluble carbodiimide (WSC) prevents voltage-dependent Ca2+ block, reduces unitary conductance, and decreases guanidinium toxin affinity. In the case of TMO, it has been suggested that all three effects result from modification of a single carboxyl group, which causes a positive shift in the channel's surface potential. We studied the effect of these reagents on Ca2+ block of adult rabbit ventricular Na+ channels in cell-attached patches. In unmodified channels, unitary conductance (gamma Na) was 18.6 +/- 0.9 pS with 280 mM Na+ and 2 mM Ca2+ in the pipette and was reduced to 5.2 +/- 0.8 pS by 10 mM Ca2+. In contrast to TTX-sensitive Na+ channels, Ca2+ block of cardiac Na+ channels was not prevented by TMO; after TMO pretreatment, gamma Na was 6.1 +/- 1.0 pS in 10 mM Ca2+. Nevertheless, TMO altered cardiac Na+ channel properties. In 2 mM Ca2+, TMO-treated patches exhibited up to three discrete gamma Na levels: 15.3 +/- 1.7, 11.3 +/- 1.5, and 9.8 +/- 1.8 pS. Patch-to-patch variation in which levels were present and the absence of transitions between levels suggests that at least two sites were modified by TMO. An abbreviation of mean open time (MOT) accompanied each decrease in gamma Na. The effects on channel gating of elevating external Ca2+ differed from those of TMO pretreatment. Increasing pipette Ca2+ from 2 to 10 mM prolonged the MOT at potentials positive to approximately -35 mV by decreasing the open to inactivated (O-->I) transition rate constant. On the other hand, even in 10 mM Ca2+ TMO accelerated the O-->I transition rate constant without a change in its voltage dependence. Ensemble averages after TMO showed a shortening of the time to peak current and an acceleration of the rate of current decay. Channel modification with WSC resulted in analogous effects to those of TMO in failing to show relief from block by 10 mM Ca2+. Further, WSC caused a decrease in gamma Na and an abbreviation of MOT at all potentials tested. We conclude that a change in surface potential caused by a single carboxyl modification is inadequate to explain the effects of TMO and WSC in heart. Failure of TMO and WSC to prevent Ca2+ block of the cardiac Na+ channel is a new distinction among isoforms in the Na+ channel multigene family.

Animals↗

PubMed1995

Modification of inactivation in cardiac sodium channels: ionic current studies with Anthopleurin-A toxin.

The site 3 toxin, Anthopleurin-A (Ap-A), was used to modify inactivation of sodium channels in voltage-clamped single canine cardiac Purkinje cells at approximately 12 degrees C. Although Ap-A toxin markedly prolonged decay of sodium current (INa) in response to step depolarizations, there was only a minor hyperpolarizing shift by 2.5 +/- 1.7 mV (n = 13) of the half-point of the peak conductance-voltage relationship with a slight steepening of the relationship from -8.2 +/- 0.8 mV to -7.2 +/- 0.8 mV (n = 13). Increases in Gmax were dependent on the choice of cation used as a Na substitute intracellularly and ranged between 26 +/- 15% (Cs, n = 5) to 77 +/- 19% (TMA, n = 8). Associated with Ap-A toxin modification time to peak INa occurred later, but analysis of the time course INa at multiple potentials showed that the largest effects were on inactivation with only a small effect on activation. Consistent with little change in Na channel activation by Ap-A toxin, INa tail current relaxations at very negative potentials, where the dominant process of current relaxation is deactivation, were similar in control and after toxin modification. The time course of the development of inactivation after Ap-A toxin modification was dramatically prolonged at positive potentials where Na channels open. However, it was not prolonged after Ap-A toxin at negative potentials, where channels predominately inactivate directly from closed states. Steady state voltage-dependent availability (h infinity or steady state inactivation), which predominately reflects the voltage dependence of closed-closed transitions equilibrating with closed-inactivated transitions was shifted in the depolarizing direction by only 1.9 +/- 0.8 mV (n = 8) after toxin modification. The slope factor changed from 7.2 +/- 0.8 to 9.9 +/- 0.9 mV (n = 8), consistent with a prolongation of inactivation from the open state of Ap-A toxin modified channels at more depolarized potentials. We conclude that Ap-A selectively modifies Na channel inactivation from the open state with little effect on channel activation or on inactivation from closed state(s).

Animals↗

PubMed2000

Activation of Drosophila sodium channels promotes modification by deltamethrin. Reductions in affinity caused by knock-down resistance mutations.

kdr and super-kdr are mutations in houseflies and other insects that confer 30- and 500-fold resistance to the pyrethroid deltamethrin. They correspond to single (L1014F) and double (L1014F+M918T) mutations in segment IIS6 and linker II(S4-S5) of Na channels. We expressed Drosophila para Na channels with and without these mutations and characterized their modification by deltamethrin. All wild-type channels can be modified by <10 nM deltamethrin, but high affinity binding requires channel opening: (a) modification is promoted more by trains of brief depolarizations than by a single long depolarization, (b) the voltage dependence of modification parallels that of channel opening, and (c) modification is promoted by toxin II from Anemonia sulcata, which slows inactivation. The mutations reduce channel opening by enhancing closed-state inactivation. In addition, these mutations reduce the affinity for open channels by 20- and 100-fold, respectively. Deltamethrin inhibits channel closing and the mutations reduce the time that channels remain open once drug has bound. The super-kdr mutations effectively reduce the number of deltamethrin binding sites per channel from two to one. Thus, the mutations reduce both the potency and efficacy of insecticide action.

Animals↗

PubMed1990

Modifications of single acetylcholine-activated channels in BC3H-1 cells. Effects of trimethyloxonium and pH.

We have examined the effects of chemical modification with trimethyloxonium (TMO) and changes in external pH on the properties of acetylcholine (ACh)-activated channels in BC3H-1 cells, a clonal muscle cell line. TMO reacts covalently and specifically with carboxylic acid moieties in proteins to convert them to neutral methyl esters. In BC3H-1 cells TMO modification reduces the whole-cell response to ACh measured at negative membrane potentials by approximately 60%. G omega seal patch-clamp recordings of single ACh channel currents showed that the reduction in ACh sensitivity is due to alterations in both the current-carrying and the kinetic properties of the channels. Under all our experimental conditions, i.e., in external solutions of normal or low ionic strength, with or without external divalent cations, and at external pHs between 5.5 and 8.1, TMO treatment reduced ACh single-channel conductance to 70-90% of normal. The effects of TMO on channel kinetics were dependent on the ionic conditions. In normal ionic strength solutions containing both calcium and magnesium ions TMO modification reduced the channel average open time by approximately 25%. A similar reduction in open time was seen in calcium-free solution, but was not present when both calcium and magnesium ions were absent from the external solution. Lowering the ionic strength of the solution increased the mean open time in normal channels by about threefold, but did not affect the kinetics of modified channels. In low ionic strength solutions normal ACh channel open times were maximal at approximately pH 6.7 and decreased by three- to fourfold at both acid and alkaline pH. TMO modification removed the pH dependence of channel kinetics, and average open times were short at all pHs between 5.5 and 8.1. We suggest that TMO modifies normally titratable groups on the external surface of ACh channels that help to determine both the gating and permeability properties of ACh channels.

Acetylcholine↗

PubMed2006

Divergent outcomes of reinforcement speciation: the relative importance of assortative mating and migration modification.

Most studies of reinforcement speciation focus on the evolution of assortative mating, but R. A. Fisher argued that migration modification is likely to be a common alternative mechanism. Despite previous models showing that assortative mating and migration modification may both be involved in reinforcement, no one has determined their relative evolutionary importance. This is surprising because understanding the biological conditions favoring these mechanisms may explain why certain pairs of species exhibit abutting, nonoverlapping geographical ranges with habitat fidelity while other pairs coexist in sympatry with sexual isolation. In this article, we explicitly model the evolution of both mechanisms simultaneously. First, we explore how these mechanisms differ in their evolutionary dynamics. Second, we ask how they affect each other's evolution and whether the interaction alters their relative importance in reinforcement. Our results reveal that assortative mating may evolve faster and under a broader range of biological conditions than migration modification. However, direct evolutionary interactions favor migration modification when populations experience strong divergent selection. Depending on the nature of postmating isolation, these mechanisms may either interfere with each other's evolution or coevolve in the same system. These results illustrate the importance of studying multiple mechanisms of speciation simultaneously in future speciation models.

Animal Migration↗

PubMed2003

Treatment plan modification using voxel-based weighting factors/dose prescription.

Under various clinical situations, it is desirable to modify the original treatment plan to better suit the clinical goals. In this work, a method to help physicians modify treatment plans based on their clinical preferences is proposed. The method uses a weighted quadratic dose objective function. The commonly used organ-/ROI-based weighting factors are expanded to a set of voxel-based weighting factors in order to obtain greater flexibility in treatment plan modification. Two different but equivalent modification schemes based on Rustem's quadratic programming algorithms--modification of a weighting matrix and modification of prescribed doses--are presented. Case studies demonstrated the effectiveness of the two methods with regard to their capability to fine-tune treatment plans.

Algorithms↗

PubMed2002

Pharmacokinetic characteristics and biodistribution of radioiodinated chimeric TNT-1, -2, and -3 monoclonal antibodies after chemical modification with biotin.

To improve the clinical potential of monoclonal antibodies (MAbs), new methods are required to augment antibody uptake in the tumor while minimizing binding in normal tissues. Our laboratory has pioneered the use of chemical modification to accomplish this goal. Using three chimeric MAbs, chTNT-1, chTNT-2, and chTNT-3, which target solid tumors by binding to common antigens found in the central necrotic core, we now demonstrate the potential of chemical modification to improve the pharmacokinetic characteristics of these unique MAbs. To identify optimal modification conditions, TNT MAbs were reacted with biotin at various ratios and tested by clearance and biodistribution analyses. The biodistribution results revealed that the numbers of biotin molecules per MAb yielding optimal tumor uptake were 3:1 for chTNT-1, 5:1 for chTNT-2, and 8:1 for chTNT-3. Biotinylated MAbs were found to have faster whole body clearance times and better biodistribution profiles compared to unmodified antibodies. Although chTNT-2 showed only a modest improvement after biotinylation, biodistribution results indicated that this MAb had the highest uptake in tumor. By reducing the charge of the antibody molecule, chemical modification appears to be a useful method for improving the pharmacokinetics and biodistribution of TNT antibodies directed to the necrotic region of solid tumors.

Animals↗

PubMedDate not supplied

Role of reversible, thioredoxin-sensitive oxidative protein modifications in cardiac myocytes.

Reactive oxygen species (ROS) are important mediators of myocardial remodeling. However, the precise molecular mechanisms by which ROS exert their effects are incompletely understood. ROS induce oxidative posttranslational protein modifications that can regulate the function of structural, functional, and signaling proteins. For example, oxidative modification of free reactive thiols (S-thiolation) on the small G protein Ras increases Ras activity and thereby promotes ROS-dependent hypertrophic signaling in cardiac myocytes. By reducing thiols and restoring reversible thiol modifications, thioredoxin and glutaredoxin can act as regulators of ROS-mediated protein function. Understanding the regulation and functional relevance of oxidative protein modifications in myocardial remodeling may lead to new therapeutic strategies.

Animals↗

PubMed1982

Chemical modification of mouse interferons.

Mouse interferon (MuIFN) preparations containing both the alpha and beta species were treated with chemical modifying reagents specific for lysine, cysteine and tryptophan residues. The purpose was to ascertain whether reagents which modify specific amino acid residues distinguished MuIFN-alpha from MuIFN-beta, and if biologic properties could be correlated with specific amino acid residues. MuIFN species were characterized by their activity on homologous and heterologous cells and by antibody neutralization. Modification of lysine residues with increasing concentrations of fluorescamine resulted in a concomitant loss of biologic and antigenic activities of both MuIFN species. Modification of cysteine residues with 5,5'-dithio-bis (2-nitrobenzoic acid) showed an enhancement of antiviral activity of MuIFN-alpha but a gradual decrease in all activities of MuIFN-beta. Modification of tryptophan residues with 2-methoxy-5-nitrobenzyl bromide enhanced somewhat MuIFN-alpha activity, but resulted in the loss of MuIFN-beta activity. These results show that amino-modifying reagents rendered both major species of MuIFN inactive; however, they can be distinguished by reagents which affect cysteine and tryptophan residues. The fact that biologic activity is accompanied by the loss of antigenicity implies that the biologic and antigenic sites may be the same or closely associated. Chemical modification of interferons may provide a useful approach for relating the properties of interferons to their primary structure.

Amino Acid Sequence↗

PubMed1997

Posttranslational modification of tubulin by palmitoylation: I. In vivo and cell-free studies.

It is well established that microtubules interact with intracellular membranes of eukaryotic cells. There is also evidence that tubulin, the major subunit of microtubules, associates directly with membranes. In many cases, this association between tubulin and membranes involves hydrophobic interactions. However, neither primary sequence nor known posttranslational modifications of tubulin can account for such an interaction. The goal of this study was to determine the molecular nature of hydrophobic interactions between tubulin and membranes. Specifically, I sought to identify a posttranslational modification of tubulin that is found in membrane proteins but not in cytoplasmic proteins. One such modification is the covalent attachment of the long chain fatty acid palmitate. The possibility that tubulin is a substrate for palmitoylation was investigated. First, I found that tubulin was palmitoylated in resting platelets and that the level of palmitoylation of tubulin decreased upon activation of platelets with thrombin. Second, to obtain quantities of palmitoylated tubulin required for protein structure analysis, a cell-free system for palmitoylation of tubulin was developed and characterized. The substrates for palmitoylation were nonpolymerized tubulin and tubulin in microtubules assembled with the slowly hydrolyzable GTP analogue guanylyl-(alpha, beta)-methylene-diphosphonate. However, tubulin in Taxol-assembled microtubules was not a substrate for palmitoylation. Likewise, palmitoylation of tubulin in the cell-free system was specifically inhibited by the antimicrotubule drugs Colcemid, podophyllotoxin, nocodazole, and vinblastine. These experiments identify a previously unknown posttranslational modification of tubulin that can account for at least one type of hydrophobic interaction with intracellular membranes.

Animals↗

PubMed2005

Dietary carbohydrate modification enhances insulin secretion in persons with the metabolic syndrome.

BACKGROUND: The metabolic syndrome markedly increases the risk of type 2 diabetes and cardiovascular disease, but the influence of dietary modification on insulin and glucose metabolism independent of weight loss is still poorly understood. OBJECTIVE: Our aim was to test whether carbohydrate dietary modifications improve insulin sensitivity and secretion and glucose tolerance in overweight or obese persons with the metabolic syndrome, even in the absence of weight loss. DESIGN: We assessed the effect of carbohydrate modification on insulin and glucose metabolism in 72 overweight or obese men and women with the metabolic syndrome, as determined according to the National Cholesterol Education Program criteria. The subjects were randomly assigned to 12-wk diets in which either rye bread and pasta or oat and wheat bread and potato were the main carbohydrate sources (34% and 37% of energy intake, respectively). RESULTS: Body weight did not significantly change in either group during the trial. No significant difference was observed in the changes in fasting glucose and insulin concentrations or in glucose and insulin areas under the curve between the groups during a 2-h oral-glucose-tolerance test. The insulinogenic index (an index of early insulin secretion) increased more in the rye bread and pasta group than in the oat and wheat bread and potato group (33.2% compared with 5.5%; P = 0.026). In the combined groups, an enhanced insulinogenic index was associated with improved glucose tolerance, whereas weight gain worsened glucose tolerance. Moreover, even modest weight gains abolished the relative improvement in the insulinogenic index in the rye bread and pasta group compared with the oat and wheat bread and potato group (P for the interaction between weight change and group = 0.019). CONCLUSIONS: Rye bread and pasta-based carbohydrate modification enhances early insulin secretion in persons with the metabolic syndrome, which may lower the risk of deteriorating glucose tolerance and development of type 2 diabetes.

Adult↗

PubMed2006

Interaction between cholesterol and glucose metabolism during dietary carbohydrate modification in subjects with the metabolic syndrome.

BACKGROUND: Carbohydrate modification based on rye bread and pasta enhances early insulin secretion in subjects with the metabolic syndrome. OBJECTIVE: Because the actions of insulin and cholesterol metabolism are interrelated, the question is raised of whether it is possible to alter cholesterol metabolism by means of dietary carbohydrate modification. DESIGN: We investigated the 12-wk effects of dietary carbohydrate modification on cholesterol synthesis and absorption by measuring the ratios of surrogate markers of precursor (cholestenol, desmosterol, and lathosterol) and absorption (cholestanol and plant sterols) sterols to cholesterol and their association to glucose metabolism in 74 subjects with the metabolic syndrome. The subjects were randomly assigned to diets with rye bread and pasta (RPa) or oat, wheat bread, and potato (OWPo) as the main carbohydrate source (34% and 37% of energy intake, respectively). RESULTS: During the study, serum cholesterol concentrations remained unchanged. Cholesterol synthesis was lower (6-10% for cholestenol and lathosterol; P < 0.05) and absorption higher (9%; P < 0.05 for sitosterol) with the OWPo diet than at baseline. With the RPa diet, cholesterol absorption was lower and synthesis higher than with the OWPo diet. The increment in the glucose area under the curve with the RPa diet was positively related to baseline cholesterol synthesis (eg, lathosterol; r = 0.480, P < 0.05) and negatively to absorption (for cholestanol; r = -0.520, P < 0.05). In the combined group, the changes in the cholestanol ratio and the insulinogenic index were interrelated (r = -0.464, P < 0.001). CONCLUSIONS: Carbohydrate modifications had dissimilar effects on cholesterol metabolism. Consumption of RPa, as compared with OWPo, may be clinically more favorable because it seems to inhibit the absorption of cholesterol, a factor crucial in the development of arterial atherosclerosis.

Adult↗

PubMed2025

Relative quantification of proteins and post-translational modifications in proteomic experiments with shared peptides: a weight-based approach.

MOTIVATION: Bottom-up mass spectrometry-based proteomics studies changes in protein abundance and structure across conditions. Since the currency of these experiments are peptides, i.e. subsets of protein sequences that carry the quantitative information, conclusions at a different level must be computationally inferred. The inference is particularly challenging in situations where the peptides are shared by multiple proteins or post-translational modifications. While many approaches infer the underlying abundances from unique peptides, there is a need to distinguish the quantitative patterns when peptides are shared. RESULTS: We propose a statistical approach for estimating protein abundances, as well as site occupancies of post-translational modifications, based on quantitative information from shared peptides. The approach treats the quantitative patterns of shared peptides as convex combinations of abundances of individual proteins or modification sites, and estimates the abundance of each source in a sample together with the weights of the combination. In simulation-based evaluations, the proposed approach improved the precision of estimated fold changes between conditions. We further demonstrated the practical utility of the approach in experiments with diverse biological objectives, ranging from protein degradation and thermal proteome stability, to changes in protein post-translational modifications. AVAILABILITY AND IMPLEMENTATION: The approach is implemented in an open-source R package MSstatsWeightedSummary. The package is currently available at https://github.com/Vitek-Lab/MSstatsWeightedSummary (doi: 10.5281/zenodo.14662989). Code required to reproduce the results presented in this article can be found in a repository https://github.com/mstaniak/MWS_reproduction (doi: 10.5281/zenodo.14656053).

Protein Processing, Post-Translational↗

PubMed2026

DirectASRM: uncovering allele-specific post-transcriptional RNA modifications through direct RNA sequencing.

SUMMARY: We developed DirectASRM, a comprehensive database for the systematic identification, integration, and annotation of allele-specific RNA modifications (ASRMs) from direct RNA sequencing data. DirectASRM enables single-base, transcript-level detection of ASRMs across multiple RNA modification types, diverse organisms and condition-specific contexts. The database further evaluates the confidence of each ASRM-SNP pair association within isoform context by jointly considering statistical evidence of allelic modification imbalance and independent support from external next-generation sequencing (NGS) - based RNA modification resources. DirectASRM also provides extensive functional annotations for ASRMs and their associated variants, including intra-sample transcript-level allele-specific expression (ASE) and allele-specific splicing, as well as additional post-transcriptional regulatory features such as miRNA binding, circRNA, RNA-protein interactions, and disease relevance. Overall, DirectASRM serves as a comprehensive resource that supports systematic investigation of the potential functional impact of genetic variants in epitranscriptomic regulation. AVAILABILITY AND IMPLEMENTATION: DirectASRM database is freely accessible at http://modinfor.com/DirectASRM/. DirectASRM pipeline is available at GitHub (https://github.com/jiayin1101/DirectASRM_pipeline) and Zenodo (DOI: https://doi.org/10.5281/zenodo.19876077).

Alleles↗

PubMed2003

A suffix tree approach to the interpretation of tandem mass spectra: applications to peptides of non-specific digestion and post-translational modifications.

MOTIVATION: Tandem mass spectrometry combined with sequence database searching is one of the most powerful tools for protein identification. As thousands of spectra are generated by a mass spectrometer in one hour, the speed of database searching is critical, especially when searching against a large sequence database, or when the peptide is generated by some unknown or non-specific enzyme, even or when the target peptides have post-translational modifications (PTM). In practice, about 70-90% of the spectra have no match in the database. Many believe that a significant portion of them are due to peptides of non-specific digestions by unknown enzymes or amino acid modifications. In another case, scientists may choose to use some non-specific enzymes such as pepsin or thermolysin for proteolysis in proteomic study, in that not all proteins are amenable to be digested by some site-specific enzymes, and furthermore many digested peptides may not fall within the rang of molecular weight suitable for mass spectrometry analysis. Interpreting mass spectra of these kinds will cost a lot of computational time of database search engines. OVERVIEW: The present study was designed to speed up the database searching process for both cases. More specifically speaking, we employed an approach combining suffix tree data structure and spectrum graph. The suffix tree is used to preprocess the protein sequence database, while the spectrum graph is used to preprocess the tandem mass spectrum. We then search the suffix tree against the spectrum graph for candidate peptides. We design an efficient algorithm to compute a matching threshold with some statistical significance level, e.g. p = 0.01, for each spectrum, and use it to select candidate peptides. Then we rank these peptides using a SEQUEST-like scoring function. The algorithms were implemented and tested on experimental data. For post-translational modifications, we allow arbitrary number of any modification to a protein. AVAILABILITY: The executable program and other supplementary materials are available online at: http://hto-c.usc.edu:8000/msms/suffix/.

Algorithms↗