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Article ; Online: Bioinformatic analysis of 302 reactive metabolite target proteins. Which ones are important for cell death?

Hanzlik, Robert P / Koen, Yakov M / Fang, Jianwen

Toxicological sciences : an official journal of the Society of Toxicology

2013 Volume 135, Issue 2, Page(s) 390–401

Abstract: Many low molecular weight compounds undergo biotransformation to chemically reactive metabolites (CRMs) that covalently modify cellular proteins. However, the mechanisms by which this covalent binding leads to cytotoxicity are not understood. Prior ... ...

Abstract	Many low molecular weight compounds undergo biotransformation to chemically reactive metabolites (CRMs) that covalently modify cellular proteins. However, the mechanisms by which this covalent binding leads to cytotoxicity are not understood. Prior analyses of lists of target proteins sorted by functional categories or hit frequency have not proven informative. In an attempt to move beyond covalent binding, we hypothesized that xenobiotic posttranslational modification of proteins might disrupt important protein-protein interactions (PPIs) and thereby direct cells from homeostasis into cell death pathways. To test this hypothesis, we analyzed a list of 302 proteins (66% rat, 26% mouse, 5% human) known to be targeted by 41 different cytotoxic CRMs. Human orthologs of rodent proteins were found by blast sequence alignment, and their interacting partners were found using the Human Protein Reference Database. The combined set of target orthologs and partners was sorted into KEGG pathways and Gene Ontology categories. Those most highly ranked based on sorting statistics and toxicological relevance were heavily involved with intracellular signaling pathways, protein folding, unfolded protein response, and regulation of apoptosis. Detailed examination revealed that many of the categories were flagged primarily by partner proteins rather than target proteins and that a majority of these partners interacted with just a small number of proteins in the CRM target set. A similar analysis performed without the partner proteins flagged very few categories as significant. These results support the hypothesis that disruption of important PPIs may be a major mechanism contributing to CRM-induced acute cytotoxicity.
MeSH term(s)	Animals ; Cell Death ; Computational Biology ; Humans ; Mice ; Proteins/metabolism ; Rats
Chemical Substances	Proteins
Language	English
Publishing date	2013-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kft166
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Article ; Online: Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners

Hanzlik Robert P / Koen Yakov M / Fang Jianwen

BMC Chemical Biology, Vol 9, Iss 1, p

2009 Volume 5

Abstract: Abstract Background Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is ... ...

Abstract	Abstract Background Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity. Results Sorting 171 known reactive metabolite target proteins revealed a number of GO categories and KEGG pathways to be significantly enriched in targets, but in most cases the classes were too large, and the "percent coverage" too small, to allow meaningful conclusions about mechanisms of toxicity. However, a similar analysis of the directlyinteracting partners of 28 common targets of multiple reactive metabolites revealed highly significant enrichments in terms likely to be highly relevant to cytotoxicity (e.g., MAP kinase pathways, apoptosis, response to unfolded protein). Machine learning was used to rank the contribution of 211 computed protein features to determining protein susceptibility to adduction. Protein lysine (but not cysteine) content and protein instability index (i.e., rate of turnover in vivo) were among the features most important to determining susceptibility. Conclusion As yet there is no good explanation for why some low-abundance proteins become heavily adducted while some abundant proteins become only lightly adducted in vivo. Analyzing the directly interacting partners of target proteins appears to yield greater insight into mechanisms of toxicity than analyzing target proteins per se. The insights provided can readily be formulated as hypotheses to test in future experimental studies.
Keywords	Biochemistry ; QD415-436 ; Organic chemistry ; QD241-441 ; Chemistry ; QD1-999 ; Science ; Q ; DOAJ:Biochemistry ; DOAJ:Life Sciences ; DOAJ:Biology and Life Sciences
Subject code	500
Language	English
Publishing date	2009-06-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Comparative Toxicity and Metabolism of N-Acyl Homologues of Acetaminophen and Its Isomer 3'-Hydroxyacetanilide.

Koen, Yakov M / Liu, Ke / Shinogle, Heather / Williams, Todd D / Hanzlik, Robert P

Chemical research in toxicology

2016 Volume 29, Issue 11, Page(s) 1857–1864

Abstract: The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in ... ...

Abstract	The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP. PYPAP and PYMAP also underwent N-deacylation followed by O-sulfation and/or N-acetylation to a modest extent. The overall rates of metabolism in hepatocytes varied approximately 2-fold in the order APAP < AMAP ≈ PYPAP < PYMAP. Rat liver microsomes supplemented with NADPH and GSH converted APAP and PYPAP to their respective glutathione conjugates (formed via a reactive quinoneimine intermediate). With PYPAP only, a hydroxylated GSH conjugate was also observed. Thus, differences in biotransformation among these analogues were modest and mostly quantitative in nature. Cytotoxicity was evaluated in cultured hepatocytes by monitoring cell death using time-lapse photomicrography coupled with Hoechst 33342 and CellTox Green dyes to facilitate counting live cells vs dead cells, respectively. Progress curves for cell death and the areas under those curves showed that toxicity was markedly dependent on compound, concentration, and time. AMAP was essentially equipotent with APAP. Homologating the acyl side chain from C-2 to C-5 led to progressive increases in toxicity up to 80-fold in the para series. In conclusion, whereas N- or ring-substitution on APAP decrease metabolism and toxicity, homologating the N-acyl side chain increases metabolism about 2-fold, preserves the chemical reactivity of quinoneimine metabolites, and increases toxicity by up to 80-fold.
MeSH term(s)	Acetaminophen/metabolism ; Acetaminophen/toxicity ; Animals ; Biotransformation ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Isomerism ; Male ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Acetaminophen (362O9ITL9D)
Language	English
Publishing date	2016-11-21
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.6b00270
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Article ; Online: Protein Targets of Isoniazid-Reactive Metabolites in Mouse Liver in Vivo.

Koen, Yakov M / Galeva, Nadezhda A / Metushi, Imir G / Uetrecht, Jack / Hanzlik, Robert P

Chemical research in toxicology

2016 Volume 29, Issue 6, Page(s) 1064–1072

Abstract: Isoniazid (INH) has been a first-line drug for the treatment of tuberculosis for more than 40 years. INH is well-tolerated by most patients, but some patients develop hepatitis that can be severe in rare cases or after overdose. The mechanisms underlying ...

Abstract	Isoniazid (INH) has been a first-line drug for the treatment of tuberculosis for more than 40 years. INH is well-tolerated by most patients, but some patients develop hepatitis that can be severe in rare cases or after overdose. The mechanisms underlying the hepatotoxicity of INH are not known, but covalent binding of reactive metabolites is known to occur in animals and is suspected in human cases. A major unresolved question is the identity of the liver proteins that are modified by INH metabolites. Treating mice with INH leads to accumulation of isonicotinoyl-lysine residues on numerous proteins in the hepatic S9 fraction. Analysis of this fraction by SDS-PAGE followed by tryptic digestion of bands and LC-MS/MS revealed a single adducted peptide derived from d-dopachrome decarboxylase. When a tryptic digest of whole S9 was applied to anti-INH antibody immobilized on beads, only 12 peptides were retained, 5 of which clearly contained isonicotinoyl-lysine adducts and could be confidently assigned to 5 liver proteins. In another experiment, undigested S9 fractions from INA-treated and untreated (UT) mice were adsorbed in parallel on anti-INA beads and the retained proteins were digested and analyzed by LC-MS/MS. The INA-S9 digest showed 1 adducted peptide that was associated with a unique protein whose identity was corroborated by numerous nonadducted peptides in the digest and 13 other proteins identified only by multiple nonadducted peptides. None of these 14 proteins was associated with any peptides present in the UT-S9 fraction. Overall, we identified 7 mouse liver proteins that became adducted by INH metabolites in vivo. Of these 7 INH target proteins, only 2 have been previously reported as targets of any reactive metabolite in vivo.
MeSH term(s)	Animals ; Antitubercular Agents/chemistry ; Antitubercular Agents/metabolism ; Antitubercular Agents/toxicity ; Female ; Isoniazid/chemistry ; Isoniazid/metabolism ; Isoniazid/toxicity ; Liver/drug effects ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Proteins/chemistry ; Proteins/metabolism
Chemical Substances	Antitubercular Agents ; Proteins ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2016--20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.6b00098
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Article ; Online: Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners.

Fang, Jianwen / Koen, Yakov M / Hanzlik, Robert P

BMC chemical biology

2009 Volume 9, Page(s) 5

Abstract: Background: Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly ... ...

Abstract	Background: Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity. Results: Sorting 171 known reactive metabolite target proteins revealed a number of GO categories and KEGG pathways to be significantly enriched in targets, but in most cases the classes were too large, and the "percent coverage" too small, to allow meaningful conclusions about mechanisms of toxicity. However, a similar analysis of the directlyinteracting partners of 28 common targets of multiple reactive metabolites revealed highly significant enrichments in terms likely to be highly relevant to cytotoxicity (e.g., MAP kinase pathways, apoptosis, response to unfolded protein). Machine learning was used to rank the contribution of 211 computed protein features to determining protein susceptibility to adduction. Protein lysine (but not cysteine) content and protein instability index (i.e., rate of turnover in vivo) were among the features most important to determining susceptibility. Conclusion: As yet there is no good explanation for why some low-abundance proteins become heavily adducted while some abundant proteins become only lightly adducted in vivo. Analyzing the directly interacting partners of target proteins appears to yield greater insight into mechanisms of toxicity than analyzing target proteins per se. The insights provided can readily be formulated as hypotheses to test in future experimental studies.
Language	English
Publishing date	2009-06-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2059860-9
ISSN	1472-6769 ; 1472-6769
ISSN (online)	1472-6769
ISSN	1472-6769
DOI	10.1186/1472-6769-9-5
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Article ; Online: Filling and mining the reactive metabolite target protein database.

Hanzlik, Robert P / Fang, Jianwen / Koen, Yakov M

Chemico-biological interactions

2009 Volume 179, Issue 1, Page(s) 38–44

Abstract: The post-translational modification of proteins is a well-known endogenous mechanism for regulating protein function and activity. Cellular proteins are also susceptible to post-translational modification by xenobiotic agents that possess, or whose ... ...

Abstract	The post-translational modification of proteins is a well-known endogenous mechanism for regulating protein function and activity. Cellular proteins are also susceptible to post-translational modification by xenobiotic agents that possess, or whose metabolites possess, significant electrophilic character. Such non-physiological modifications to endogenous proteins are sometimes benign, but in other cases they are strongly associated with, and are presumed to cause, lethal cytotoxic consequences via necrosis and/or apoptosis. The Reactive Metabolite Target Protein Database (TPDB) is a searchable, freely web-accessible (http://tpdb.medchem.ku.edu:8080/protein_database/) resource that attempts to provide a comprehensive, up-to-date listing of known reactive metabolite target proteins. In this report we characterize the TPDB by reviewing briefly how the information it contains came to be known. We also compare its information to that provided by other types of "-omics" studies relevant to toxicology, and we illustrate how bioinformatic analysis of target proteins may help to elucidate mechanisms of cytotoxic responses to reactive metabolites.
MeSH term(s)	Databases, Protein ; Information Storage and Retrieval ; Protein Binding
Language	English
Publishing date	2009-04-15
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2008.08.016
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Article ; Online: Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes.

Goldman, Jennifer L / Koen, Yakov M / Rogers, Steven A / Li, Kelin / Leeder, James S / Hanzlik, Robert P

Drug metabolism and disposition: the biological fate of chemicals

2016 Volume 44, Issue 10, Page(s) 1603–1607

Abstract: The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse ...

Abstract	The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [(14)C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding-induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs.
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.116.072041
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Article: Identification of seven proteins in the endoplasmic reticulum as targets for reactive metabolites of bromobenzene.

Koen, Yakov M / Hanzlik, Robert P

Chemical research in toxicology

2002 Volume 15, Issue 5, Page(s) 699–706

Abstract: The hepatotoxicity of bromobenzene is strongly correlated with the covalent binding of chemically reactive metabolites to cellular proteins, but up to now relatively few hepatic protein targets of these reactive metabolites have been identified. To ... ...

Abstract	The hepatotoxicity of bromobenzene is strongly correlated with the covalent binding of chemically reactive metabolites to cellular proteins, but up to now relatively few hepatic protein targets of these reactive metabolites have been identified. To identify additional hepatic protein targets we injected an hepatotoxic dose of [14C]bromobenzene to phenobarbital-pretreated male Sprague-Dawley rats ip. After 4 h, their livers were removed and homogenized, and the homogenates fractionated by differential ultracentrifugation. The highest specific radiolabeling (6.1 nmol equiv 14C/mg of protein) was observed in a particulate fraction (P25) sedimented at 25000g from a 6000g supernatant fraction. Proteins in this fraction were separated by two-dimensional electrophoresis and, after transblotting, analyzed for radioactivity by phosphorimaging. More than 20 radiolabeled protein spots were observed in the blots. For 17 of these spots, peptide mass maps were obtained using in-gel digestion with trypsin, followed by MALDI-TOF mass spectrometric analysis of the resulting peptide mixtures. By searching genomic databases, the 17 sets of MS-derived peptide masses were found to match predicted tryptic fragments of just 7 proteins. Spots 1-4 matched with 78 kDa glucose regulated protein (GRP78), protein disulfide isomerase isozyme A1 (PDIA1), endoplasmic reticulum protein ERp29, and PDIA6, respectively. Spots 5 and 6, 7-11, and 12-17 presented as apparent "charge trains" of spots, each of which gave peptide mixtures closely similar to those of other spots within the train. The proteins present in these sets of spots were identified as transthyretin, serum albumin precursor and PDIA3, respectively. The possible relationship of the adduction of these proteins to the toxicological outcome is discussed.
MeSH term(s)	Animals ; Bromobenzenes/metabolism ; Electrophoresis, Gel, Two-Dimensional ; Endoplasmic Reticulum/metabolism ; Liver/metabolism ; Male ; Proteins/isolation & purification ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Bromobenzenes ; Proteins ; bromobenzene (CO4D5J547L)
Language	English
Publishing date	2002-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/tx0101898
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Article: A proteomic analysis of bromobenzene reactive metabolite targets in rat liver cytosol in vivo.

Koen, Yakov M / Gogichaeva, Natalia V / Alterman, Michail A / Hanzlik, Robert P

Chemical research in toxicology

2007 Volume 20, Issue 3, Page(s) 511–519

Abstract: Metabolic activation and protein covalent binding are early and apparently obligatory events in the cytotoxicity of many simple organic chemicals including drugs and natural products. Although much has been learned about the chemistry of reactive ... ...

Abstract	Metabolic activation and protein covalent binding are early and apparently obligatory events in the cytotoxicity of many simple organic chemicals including drugs and natural products. Although much has been learned about the chemistry of reactive metabolite formation and reactivity toward protein nucleophiles, progress in identifying specific protein targets for reactive metabolites of various protoxins has been much slower. We previously reported nine microsomal and three cytosolic proteins as targets for reactive metabolites of bromobenzene in rat liver. These results, and contemporary work by others, indicate that protein covalent binding is not totally random in cells. Moreover, as protein targets for other protoxins were identified, little commonality of target proteins became apparent. In the present work, we used two-dimensional gel electrophoresis to separate liver cytosolic proteins from rats treated with 14C-bromobenzene; 110 of the 836 observed spots contained measurable radioactivity that varied over a 600-fold range of adduct density. Of these 110 spots, in-gel digestion coupled with mass spectrometry identified apparently single proteins in 57 spots. A few other spots clearly contained more than one identifiable protein, and in several cases, the same protein was identified in several spots having different apparent molecular masses and/or pI. Altogether, 33 unique new protein targets for bromobenzene metabolites were identified and compared to those known for acetaminophen, naphthalene, butylated hydroxytoluene, benzene, thiobenzamide, and halothane via a target protein database available at http://tpdb.medchem.ku.edu:8080/protein_database/. With increasing numbers of target proteins becoming known, more commonality in targeting by reactive metabolites from diverse chemical agents may be seen. Such commonality may help to separate toxicologically significant covalent binding events from a background of covalent binding that is toxicologically inconsequential.
MeSH term(s)	Animals ; Bromine/chemistry ; Bromobenzenes/chemistry ; Cytosol/drug effects ; Cytosol/metabolism ; Databases, Protein ; Electrophoresis, Polyacrylamide Gel ; Hydrolysis ; In Vitro Techniques ; Liver/drug effects ; Liver/metabolism ; Male ; Proteomics ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Subcellular Fractions/drug effects ; Subcellular Fractions/enzymology ; Subcellular Fractions/metabolism ; Trypsin
Chemical Substances	Bromobenzenes ; bromobenzene (CO4D5J547L) ; Trypsin (EC 3.4.21.4) ; Bromine (SBV4XY874G)
Language	English
Publishing date	2007-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/tx6003166
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Article ; Online: The reactive metabolite target protein database (TPDB) – a web-accessible resource

Dong Yinghua / Theertham Bhargav / Koen Yakov M / Hanzlik Robert P / Fang Jianwen

BMC Bioinformatics, Vol 8, Iss 1, p

2007 Volume 95

Abstract: Abstract Background The toxic effects of many simple organic compounds stem from their biotransformation to chemically reactive metabolites which bind covalently to cellular proteins. To understand the mechanisms of cytotoxic responses it may be ... ...

Abstract	Abstract Background The toxic effects of many simple organic compounds stem from their biotransformation to chemically reactive metabolites which bind covalently to cellular proteins. To understand the mechanisms of cytotoxic responses it may be important to know which proteins become adducted and whether some may be common targets of multiple toxins. The literature of this field is widely scattered but expanding rapidly, suggesting the need for a comprehensive, searchable database of reactive metabolite target proteins. Description The Reactive Metabolite Target Protein Database (TPDB) is a comprehensive, curated, searchable, documented compilation of publicly available information on the protein targets of reactive metabolites of 18 well-studied chemicals and drugs of known toxicity. TPDB software enables i) string searches for author names and proteins names/synonyms, ii) more complex searches by selecting chemical compound, animal species, target tissue and protein names/synonyms from pull-down menus, and iii) commonality searches over multiple chemicals. Tabulated search results provide information, references and links to other databases. Conclusion The TPDB is a unique on-line compilation of information on the covalent modification of cellular proteins by reactive metabolites of chemicals and drugs. Its comprehensiveness and searchability should facilitate the elucidation of mechanisms of reactive metabolite toxicity. The database is freely available at http://tpdb.medchem.ku.edu/tpdb.html
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2007-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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