Structural Shifts of Aldehyde Dehydrogenase Enzymes Were Instrumental for the Early Evolution of Retinoid- Dependent Axial Patterning in Metazoans

Total Page:16

File Type:pdf, Size:1020Kb

Structural Shifts of Aldehyde Dehydrogenase Enzymes Were Instrumental for the Early Evolution of Retinoid- Dependent Axial Patterning in Metazoans Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid- dependent axial patterning in metazoans Tiago J. P. Sobreiraa,1, Ferdinand Marlétazb,1, Marcos Simões-Costac,d,1, Deborah Schechtmane, Alexandre C. Pereiraa, Frédéric Brunetb, Sarah Sweeneyf, Ariel Panig,h, Jochanan Aronowiczh, Christopher J. Loweh, Bradley Davidsonf, Vincent Laudetb, Marianne Bronneri, Paulo S. L. de Oliveiraa, Michael Schubertb,2,3, and José Xavier-Netoc,2,3 aLaboratório de Genética e Cardiologia Molecular, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000, São Paulo-SP, Brazil; bInstitut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France; cLaboratório Nacional de Biociências, Campus do Laboratório Nacional de Luz Síncrotron, 13083-970, Campinas-SP, Brazil; dDepartamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, University of São Paulo, 05508-900, São Paulo-SP, Brazil; eDepartamento de Bioquímica, Instituto de Química da Universidade de São Paulo, 05508-900, São Paulo-SP, Brazil; fDepartment of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85724; gCommittee on Evolutionary Biology, University of Chicago, Chicago, IL 60637; hHopkins Marine Station, Department of Biology, Stanford University, Pacific Grove, CA 93950; and iDivision of Biology 139-74, California Institute of Technology, Pasadena, CA 91125 Edited* by John Gerhart, University of California, Berkeley, CA, and approved November 10, 2010 (received for review August 17, 2010) Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and Second, ALDHs are among the best-characterized proteins, and process the vitamin A-derived retinaldehyde into retinoic acid (RA), their structure and substrate profiles have been determined with a small diffusible molecule and a pivotal chordate morphogen. In exquisite precision (9–15). Thus, structural modeling of these this study, we combine phylogenetic, structural, genomic, and de- proteins can be used to study the evolution of substrate specificity velopmental gene expression analyses to examine the evolutionary without extensive biochemical analyses (16–20). origins of ALDH substrate preference. Structural modeling reveals ALDH1 and ALDH2 enzymes share a high degree of sequence that processing of small aldehydes, such as acetaldehyde, by identity, indicating a very close phylogenetic relationship (3). Pi- ALDH2, versus large aldehydes, including retinaldehyde, by oneer observations by Moore et al. on human ALDH2 and sheep EVOLUTION ALDH1A is associated with small versus large substrate entry chan- ALDH1 (17) suggested that their respective abilities to detoxify nels (SECs), respectively. Moreover, we show that metazoan small aldehydes and to process large aldehydes are correlated with ALDH1s and ALDH2s are members of a single ALDH1/2 clade and the size and shape of their substrate entry channels (SECs), the that during evolution, eukaryote ALDH1/2s often switched be- intramolecular cavities that direct aldehydes to the catalytic sites of ALDH enzymes. Human ALDH2 displays a narrow SEC with tween large and small SECs after gene duplication, transforming a constricted entrance, whereas sheep ALDH1A1 exhibits a large constricted channels into wide opened ones and vice versa. Ances- SEC with a broad opening (17, 18). Thus, SEC topology influences tral sequence reconstructions suggest that during the evolutionary ALDH1/2 substrate preference. For example, although reti- emergence of RA signaling, the ancestral, narrow-channeled meta- naldehyde is a good substrate for vertebrate ALDH1s and acet- zoan ALDH1/2 gave rise to large ALDH1 channels capable of accom- aldehyde is a natural substrate of ALDH2s, ALDH2s cannot modating bulky aldehydes, such as retinaldehyde, supporting the process retinaldehyde and ALDH1s process acetaldehyde only view that retinoid-dependent signaling arose from ancestral cellu- extremely inefficiently (16, 17–22). lar detoxification mechanisms. Our analyses also indicate that, on To understand the evolutionary origins of the substrate pref- a more restricted evolutionary scale, ALDH1 duplicates from inver- erences of ALDH1 and ALDH2 enzymes, as well as to illuminate tebrate chordates (amphioxus and ascidian tunicates) underwent how signaling and protective functions are connected to these switches to smaller and narrower SECs. When combined with alter- different enzyme activities, we used an integrated approach that ations in gene expression, these switches led to neofunctionaliza- combined genomic, phylogenetic, and structural analyses. The tion from ALDH1-like roles in embryonic patterning to systemic, resulting comprehensive data set was complemented with in- ALDH2-like roles, suggesting functional shifts from signaling to formation on developmental gene expression of ALDH1/2s in the detoxification. cephalochordate amphioxus (Branchiostoma floridae) and the ascidian tunicate Ciona intestinalis. These two invertebrate chor- Aldehyde dehydrogenase phylogeny | Branchiostoma floridae | Ciona date models possess functional RA signaling cascades and are intestinalis versus Ciona savignyi | evolution of retinoic acid signaling | pivotal models for understanding vertebrate origins from both origins of morphogen-dependent signaling a genomic and a developmental perspective (4, 23–26). Together, this work provides support for the hypothesis that some in- tercellular signaling mechanisms evolved from cellular de- n animal development, major signaling pathways are controlled fi Iby morphogens, diffusible molecules whose evolutionary origins toxi cation pathways. are difficult to assess. Aldehyde dehydrogenase (ALDH) enzymes are attractive subjects to study the evolution of morphogen sig- naling for two main reasons. First, in addition to their acknowl- Author contributions: M.S. and J.X.-N. designed research; T.J.P.S., F.M., M.S.-C., D.S., F.B., S.S., A.P., J.A., C.J.L., B.D., P.S.L.d.O., M.S., and J.X.-N. performed research; D.S., C.J.L., B.D., edged role in protecting animals by catabolizing reactive biogenic M.B., and P.S.L.d.O. contributed new reagents/analytic tools; T.J.P.S., F.M., M.S.-C., D.S., and xenobiotic aldehydes, some ALDHs also synthesize signaling A.C.P., F.B., S.S., A.P., J.A., C.J.L., B.D., V.L., P.S.L.d.O., M.S., and J.X.-N. analyzed data; and molecules (1–3). Prime examples for these two ALDH enzyme T.J.P.S., F.M., D.S., B.D., V.L., M.B., P.S.L.d.O., M.S., and J.X.-N. wrote the paper. roles are the ALDH2s, which degrade small toxic aldehydes, The authors declare no conflict of interest. such as the acetaldehyde derived from ethanol metabolism (1, 2), *This Direct Submission article had a prearranged editor. and the ALDH1s, which process larger aldehydes, including ret- 1T.J.P.S., F.M., and M.S.-C. contributed equally to this work. inaldehyde, a vitamin A-derived precursor of the morphogen 2M.S. and J.X.-N. contributed equally to this work. retinoic acid (RA). RA plays a critical role during embryonic 3To whom correspondence may be addressed. E-mail: [email protected] or development of chordates (i.e., amphioxus, tunicates, and verte- [email protected]. brates) and has been suggested to have already been involved in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. patterning the last common ancestor of bilaterian animals (4–8). 1073/pnas.1011223108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1011223108 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 Results we performed large-scale phylogenetic analyses of the ALDH SEC Volumes Distinguish Vertebrate ALDH1s from ALDH2s. To test superfamily (Fig. 1, Figs. S1 and S2, Dataset S1, and Dataset S2). whether SEC differences between sheep ALDH1 and human Contrary to traditional views, we found that metazoan ALDH1s ALDH2 reflect fundamental evolutionary differences between and ALDH2s do not form independent families but are members these enzymes, we used the crystal structures of these proteins to of a single, well-supported ALDH1/2 clade, with ALDH2s create 3D structural models of ALDH1/2s. These models were forming a distinct group nested within this ALDH1/2 clade (Fig. 1 then analyzed to determine molecular parameters, such as SEC and Figs. S1 and S2). In contrast to ALDH2s, ALDH1s un- volume, which are implicated in substrate preference (17). Our derwent multiple lineage-specific duplications. For example, the dataset shows that ALDH1s generally display larger channel genomes of amphioxus (B. floridae) and the ascidian tunicates volumes than ALDH2s (589 ± 59 Å3 for ALDH1s versus 403 ± C. intestinalis and C. savignyi contain, respectively, six, four, and 53 Å3 for ALDH2s, mean ± SD, P < 0.001) (Dataset S1 and two ALDH1 duplicates, whereas in the hemichordate Saccoglossus Dataset S2). Therefore, channel volume represents a funda- kowalevskii, there are five ALDH1 genes (Fig. 1, Figs. S1 and S2, mental difference between ALDH1 and ALDH2, reflecting Dataset S1, and Dataset S2) (27). conserved structural requirements associated with processing of Analyses of channel size distribution in eukaryote ALDH1s large and small aldehydes, respectively. and ALDH2s indicate that SEC variation can be subdivided into small (<420 Å3), medium (420–508 Å3), and large channels Because it is likely that the overall geometry of the SEC, rather 3 than its volume alone, determines ALDH1/2 specificities, we (>508 Å )(Fig. S3,
Recommended publications
  • (ALDH1A3) for the Maintenance of Non-Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway
    Author Manuscript Published OnlineFirst on June 6, 2014; DOI: 10.1158/1078-0432.CCR-13-3292 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Essential role of aldehyde dehydrogenase 1A3 (ALDH1A3) for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway Chunli Shao1,2, James P. Sullivan3, Luc Girard1,2, Alexander Augustyn1,2, Paul Yenerall1,2, Jaime Rodriguez4, Hui Liu4, Carmen Behrens4, Jerry W. Shay5, Ignacio I. Wistuba4, John D. Minna 1,2,6,7 1Hamon Center for Therapeutic Oncology Research, 2Simmons Comprehensive Cancer Center, 3Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, 4Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77054, 5Department of Cell Biology, 6Department of Pharmacology, 7Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA. Running Title: ALDH1A3 in non-small cell lung cancer stem cells Keywords: Lung cancer, cancer stem cells, ALDH1A3, STAT3, Stattic Financial Support This project was supported by CPRIT, NCI SPORE P50CA70907, UTSW Cancer Center Support Grant 5P30-CA142543, and the Gillson-Longenbaugh Foundation. Address Correspondence: John D. Minna, M.D. 6000 Harry Hines Blvd Dallas, TX 75390-8593 Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Phone: 214-648-4900; Fax: 214-648-4940 [email protected] Disclosure of Potential Conflict of Interest The authors indicate no potential conflicts of interest. Word count: 4583 Total number of figures and tables: 6 figures Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research.
    [Show full text]
  • The Aldehyde Dehydrogenase ALDH2*2 Allele Exhibits Dominance Over ALDH2*1 in Transduced Hela Cells
    The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells. Q Xiao, … , T Johnston, D W Crabb J Clin Invest. 1995;96(5):2180-2186. https://doi.org/10.1172/JCI118272. Research Article Individuals heterozygous or homozygous for the variant aldehyde dehydrogenase (ALDH2) allele (ALDH2*2), which encodes a protein differing only at residue 487 from the normal protein, have decreased ALDH2 activity in liver extracts and experience cutaneous flushing when they drink alcohol. The mechanisms by which this allele exerts its dominant effect is unknown. To study this effect, the human ALDH2*1 cDNA was cloned and the ALDH2*2 allele was generated by site-directed mutagenesis. These cDNAs were transduced using retroviral vectors into HeLa and CV1 cells, which do not express ALDH2. The normal allele directed synthesis of immunoreactive ALDH2 protein (ALDH2E) with the expected isoelectric point. Extracts of these cells contained increased aldehyde dehydrogenase activity with low Km for the aldehyde substrate. The ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein (ALDH2K), but the protein lacked enzymatic activity. When ALDH2*1-expressing cells were transduced with ALDH2*2 vectors, both mRNAs were expressed and immunoreactive proteins with isoelectric points ranging between those of ALDH2E and ALDH2K were present, indicating that the subunits formed heteromers. ALDH2 activity in these cells was reduced below that of the parental ALDH2*1-expressing cells. Thus, the ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro. Find the latest version: https://jci.me/118272/pdf The Aldehyde Dehydrogenase ALDH2*2 Allele Exhibits Dominance over ALDH2*1 in Transduced HeLa Cells Qing Xiao, * Henry Weiner,* Timothy Johnston,* and David W.
    [Show full text]
  • The Utility of Genetic Risk Scores in Predicting the Onset of Stroke March 2021 6
    DOT/FAA/AM-21/24 Office of Aerospace Medicine Washington, DC 20591 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke Diana Judith Monroy Rios, M.D1 and Scott J. Nicholson, Ph.D.2 1. KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510 Bogotá D.C. Colombia 2. FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 March 2021 NOTICE This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest of information exchange. The United States Government assumes no liability for the contents thereof. _________________ This publication and all Office of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute’s publications Web site: (www.faa.gov/go/oamtechreports) Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. DOT/FAA/AM-21/24 4. Title and Subtitle 5. Report Date March 2021 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke 6. Performing Organization Code 7. Author(s) 8. Performing Organization Report No. Diana Judith Monroy Rios M.D1, and Scott J. Nicholson, Ph.D.2 9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 1 KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510, Bogotá D.C. Colombia 11. Contract or Grant No. 2 FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 12. Sponsoring Agency name and Address 13. Type of Report and Period Covered Office of Aerospace Medicine Federal Aviation Administration 800 Independence Ave., S.W.
    [Show full text]
  • ATAP00021-Recombinant Human ALDH1A1 Protein
    ATAGENIX LABORATORIES Catalog Number:ATAP00021 Recombinant Human ALDH1A1 protein Product Details Summary English name Recombinant Human ALDH1A1 protein Purity >90% as determined by SDS-PAGE Endotoxin level Please contact with the lab for this information. Construction A DNA sequence encoding the human ALDH1A1 (Met1-Ser501) was fused with His tag Accession # P00352 Host E.coli Species Homo sapiens (Human) Predicted Molecular Mass 52.58 kDa Formulation Supplied as solution form in PBS pH 7.5 or lyophilized from PBS pH 7.5. Shipping In general, proteins are provided as lyophilized powder/frozen liquid. They are shipped out with dry ice/blue ice unless customers require otherwise. Stability &Storage Use a manual defrost freezer and avoid repeated freeze thaw cycles. Store at 2 to 8 °C for one week . Store at -20 to -80 °C for twelve months from the date of receipt. Reconstitution Reconstitute in sterile water for a stock solution.A copy of datasheet will be provided with the products, please refer to it for details. Background Background Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), also known as Aldehyde dehydrogenase 1 (ALDH1), or Retinaldehyde Dehydrogenase 1 (RALDH1), is an enzyme that is expressed at high levels in stem cells and that has been suggested to regulate stem cell function. The retinaldehyde dehydrogenase (RALDH) subfamily of ALDHs, composed of ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1, regulate development by catalyzing retinoic acid biosynthesis. The ALDH1A1 protein belongs to the aldehyde dehydrogenases family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH1A1 also belongs to the group of corneal crystallins that Web:www.atagenix.com E-mail: [email protected] Tel: 027-87433958 ATAGENIX LABORATORIES Catalog Number:ATAP00021 Recombinant Human ALDH1A1 protein help maintain the transparency of the cornea.
    [Show full text]
  • Upregulation of ALDH1B1 Promotes Tumor Progression in Osteosarcoma
    www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 2), pp: 2502-2514 Research Paper Upregulation of ALDH1B1 promotes tumor progression in osteosarcoma Xin Wang1,*, Yan Yu2,*, Yuting He2,*, Qiqing Cai1, Songtao Gao1, Weitao Yao1, Zhiyong Liu1, Zhichao Tian1, Qicai Han3, Weiwei Wang4, Ranran Sun2, Yonggang Luo3 and Chao Li1 1Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China 2Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 3Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 4Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China *These authors have contributed equally to this work Correspondence to: Chao Li, email: [email protected] Yonggang Luo, email: [email protected] Keywords: osteosarcoma; ALDH1B1; progression; proliferation; metastasis Received: August 21, 2017 Accepted: December 04, 2017 Published: December 20, 2017 Copyright: Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood and adolescence with poor prognosis. The mechanism underlying tumorigenesis and development of OS is largely unknown. ALDH1B1 has been reported to involve in many kinds of human cancers and functions as an oncogene, but the role of ALDH1B1 in OS has not been investigated comprehensively. In the present study, we aimed to examine clinical value and biological function of ALDH1B1 in OS.
    [Show full text]
  • Volatile and Intravenous Anesthesia Alter Rat Liver Proteins: Proteomic Time Course Analysis of Rat Liver Proteins
    8 The Open Proteomics Journal, 2012, 5, 8-16 Open Access Volatile and Intravenous Anesthesia Alter Rat Liver Proteins: Proteomic Time Course Analysis of Rat Liver Proteins Hisashi Watanabe1,*, Chihiro Kamagata2, Yoshiaki Tsuboko2 and Atsuhiro Sakamoto3 1Graduate Student, Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan 2Staff Member, Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan 3Professor and Chair, Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Abstract: Background: Our previous microarray study showed that sevoflurane anesthesia affects the expression of rat genes in multiple organs including the liver. In this study, we investigated whether liver protein expression was altered after propofol, sevoflurane, or isoflurane anesthesia. We also investigated differences in the time course of each drug 24 and 72 h after anesthesia. Methods: Rats were randomly assigned to four groups (non-anesthetized group and three groups anesthetized at each time point, n = 6 per group). A venous catheter was inserted into the caudal vein of all rats. Rats were anesthetized with each agent for 6 h, and the liver was obtained immediately after anesthesia. Proteomic analysis was performed. Results: About 4200 spots in each gel were discriminated, and at least 2619 spots were matched. Using LC-MS/MS, we identified 47 spots for propofol, 45 spots for sevoflurane, and 21 spots for isoflurane that were differentially expressed (p < 0.05) 0 h after anesthesia. The numbers of altered proteins were 14 and 19 in the isoflurane and sevoflurane groups, respectively, 72 h after anesthesia, but alterations in 40 proteins were seen in the propofol group 72 h after anesthesia.
    [Show full text]
  • Supplementary Materials
    1 Supplementary Materials: Supplemental Figure 1. Gene expression profiles of kidneys in the Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice. (A) A heat map of microarray data show the genes that significantly changed up to 2 fold compared between Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice (N=4 mice per group; p<0.05). Data show in log2 (sample/wild-type). 2 Supplemental Figure 2. Sting signaling is essential for immuno-phenotypes of the Fcgr2b-/-lupus mice. (A-C) Flow cytometry analysis of splenocytes isolated from wild-type, Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice at the age of 6-7 months (N= 13-14 per group). Data shown in the percentage of (A) CD4+ ICOS+ cells, (B) B220+ I-Ab+ cells and (C) CD138+ cells. Data show as mean ± SEM (*p < 0.05, **p<0.01 and ***p<0.001). 3 Supplemental Figure 3. Phenotypes of Sting activated dendritic cells. (A) Representative of western blot analysis from immunoprecipitation with Sting of Fcgr2b-/- mice (N= 4). The band was shown in STING protein of activated BMDC with DMXAA at 0, 3 and 6 hr. and phosphorylation of STING at Ser357. (B) Mass spectra of phosphorylation of STING at Ser357 of activated BMDC from Fcgr2b-/- mice after stimulated with DMXAA for 3 hour and followed by immunoprecipitation with STING. (C) Sting-activated BMDC were co-cultured with LYN inhibitor PP2 and analyzed by flow cytometry, which showed the mean fluorescence intensity (MFI) of IAb expressing DC (N = 3 mice per group). 4 Supplemental Table 1. Lists of up and down of regulated proteins Accession No.
    [Show full text]
  • Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
    Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen,
    [Show full text]
  • Identify Distinct Prognostic Impact of ALDH1 Family Members by TCGA Database in Acute Myeloid Leukemia
    Open Access Annals of Hematology & Oncology Research Article Identify Distinct Prognostic Impact of ALDH1 Family Members by TCGA Database in Acute Myeloid Leukemia Yi H, Deng R, Fan F, Sun H, He G, Lai S and Su Y* Department of Hematology, General Hospital of Chengdu Abstract Military Region, China Background: Acute myeloid leukemia is a heterogeneous disease. Identify *Corresponding author: Su Y, Department of the prognostic biomarker is important to guide stratification and therapeutic Hematology, General Hospital of Chengdu Military strategies. Region, Chengdu, 610083, China Method: We detected the expression level and the prognostic impact of Received: November 25, 2017; Accepted: January 18, each ALDH1 family members in AML by The Cancer Genome Atlas (TCGA) 2018; Published: February 06, 2018 database. Results: Upon 168 patients whose expression level of ALDH1 family members were available. We found that the level of ALDH1A1correlated to the prognosis of AML by the National Comprehensive Cancer Network (NCCN) stratification but not in other ALDH1 members. Moreover, we got survival data from 160 AML patients in TCGA database. We found that high ALDH1A1 expression correlated to poor Overall Survival (OS), mostly in Fms-like Tyrosine Kinase-3 (FLT3) mutated group. HighALDH1A2 expression significantly correlated to poor OS in FLT3 wild type population but not in FLT3 mutated group. High ALDH1A3 expression significantly correlated to poor OS in FLT3 mutated group but not in FLT3 wild type group. There was no relationship between the OS of AML with the level of ALDH1B1, ALDH1L1 and ALDH1L2. Conclusion: The prognostic impacts were different in each ALDH1 family members, which needs further investigation.
    [Show full text]
  • Mapping Aldehyde Dehydrogenase 1A1 Activity Using an [18F]Substrate-Based Approach Raul Pereira,[A] Thibault Gendron,[B] Chandan Sanghera,[A] Hannah E
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Birkbeck Institutional Research Online DOI: 10.1002/chem.201805473 Full Paper & Biochemistry Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-Based Approach Raul Pereira,[a] Thibault Gendron,[b] Chandan Sanghera,[a] Hannah E. Greenwood,[a] Joseph Newcombe,[b, c] Patrick N. McCormick,[a] Kerstin Sander,[b] Maya Topf,[c] Erik rstad,[b] and Timothy H. Witney*[a] Abstract: Aldehyde dehydrogenases (ALDHs) catalyze the focused library of compounds evaluated, N-ethyl-6-(fluoro)- oxidation of aldehydes to carboxylic acids. Elevated ALDH N-(4-formylbenzyl)nicotinamide 4b was found to have excel- expression in human cancers is linked to metastases and lent affinity and isozyme selectivity for ALDH1A1 in vitro. poor overall survival. Despite ALDH being a poor prognostic Following 18F-fluorination, [18F]4b was taken up by colorectal factor, the non-invasive assessment of ALDH activity in vivo tumor cells and trapped through the conversion to its 18F-la- has not been possible due to a lack of sensitive and transla- beled carboxylate product under the action of ALDH. In vivo tional imaging agents. Presented in this report are the syn- positron emission tomography revealed high uptake of thesis and biological evaluation of ALDH1A1-selective chemi- [18F]4b in the lungs and liver, with radioactivity cleared cal probes composed of an aromatic aldehyde derived from through the urinary tract. Oxidation of [18F]4b, however, was N,N-diethylamino benzaldehyde (DEAB) linked to a fluorinat- observed in vivo, which may limit the tissue penetration of ed pyridine ring either via an amide or amine linkage.
    [Show full text]
  • Overall Survival of Pancreatic Ductal Adenocarcinoma Is Doubled by Aldh7a1 Deletion in the KPC Mouse
    Overall survival of pancreatic ductal adenocarcinoma is doubled by Aldh7a1 deletion in the KPC mouse Jae-Seon Lee1,2*, Ho Lee3*, Sang Myung Woo4, Hyonchol Jang1, Yoon Jeon1, Hee Yeon Kim1, Jaewhan Song2, Woo Jin Lee4, Eun Kyung Hong5, Sang-Jae Park4, Sung- Sik Han4§§ and Soo-Youl Kim1§ 1Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea. 2Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. 3Graduate School of Cancer Science and Policy, 4Department of Surgery, Center for Liver and Pancreatobiliary Cancer and 5Department of Pathology, National Cancer Center, Goyang, Republic of Korea. Correspondence §Corresponding author: [email protected] (S.-Y.K.) §§Co-corresponding author: [email protected] (S.-S.H.) *These authors contributed equally to this work 1 Abstract Rationale: The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic ductal adenocarcinoma (PDAC). ALDH7A1 knockdown significantly reduced tumor formation in PDAC. We raised a question how ALDH7A1 contributes to cancer progression. Methods: To answer the question, the role of ALDH7A1 in energy metabolism was investigated by knocking down and knockdown gene in mouse model, because the role of ALDH7A1 has been reported as a catabolic enzyme catalyzing fatty aldehyde from lipid peroxidation to fatty acid. Oxygen consumption rate (OCR), ATP production, mitochondrial membrane potential, proliferation assay and immunoblotting were performed. In in vivo study, two human PDAC cell lines were used for pre-clinical xenograft model as well as spontaneous PDAC model of KPC mice was also employed for anti-cancer therapeutic effect.
    [Show full text]
  • A Missense Mutation in ALDH1A3 Causes Isolated Microphthalmia/Anophthalmia in Nine Individuals from an Inbred Muslim Kindred
    European Journal of Human Genetics (2014) 22, 419–422 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred Adi Mory1,2, Francesc X Ruiz3, Efrat Dagan2,4, Evgenia A Yakovtseva3, Alina Kurolap1, Xavier Pare´s3, Jaume Farre´s3 and Ruth Gershoni-Baruch*,1,2 Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein. European Journal of Human Genetics (2014) 22, 419–422; doi:10.1038/ejhg.2013.157; published online 24 July 2013 Keywords: ALDH1A3 gene; anophthalmia/microphthalmia; homozogosity mapping INTRODUCTION METHODS Anophthalmia and microphthalmia (A/M) are rare developmental Patients and families anomalies resulting in absent or small ocular globes, respectively.
    [Show full text]