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Functional Annotation of ABHD14B, an Orphan Serine Hydrolase Enzyme

  • Abinaya Rajendran*
    Abinaya Rajendran
    Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road Pashan, Pune 411008, Maharashtra, India
    *E-mail: [email protected]
  • Kaveri Vaidya
    Kaveri Vaidya
    Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road Pashan, Pune 411008, Maharashtra, India
  • Johnny Mendoza
    Johnny Mendoza
    Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Jennifer Bridwell-Rabb
    Jennifer Bridwell-Rabb
    Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, Ann Arbor, Michigan 48109, United States
  • , and 
  • Siddhesh S. Kamat*
    Siddhesh S. Kamat
    Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road Pashan, Pune 411008, Maharashtra, India
    *E-mail: [email protected]
Cite this: Biochemistry 2020, 59, 2, 183–196
Publication Date (Web):September 3, 2019
https://doi.org/10.1021/acs.biochem.9b00703
Copyright © 2019 American Chemical Society

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    Abstract

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    The metabolic serine hydrolase family is, arguably, one of the largest functional enzyme classes in mammals, including humans, comprising 1–2% of the total proteome. This enzyme family uses a conserved nucleophilic serine residue in the active site to perform diverse hydrolytic reactions and consists of proteases, lipases, esterases, amidases, and transacylases, which are prototypical members of this family. In humans, this enzyme family consists of >250, of which approximately 40% members remain unannotated, in terms of both their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAFII250-interacting factor B, as it was found to be associated with transcription initiation factor TFIID. The crystal structure of human ABHD14B was determined more than a decade ago; however, its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme’s ability to transfer an acetyl group from a post-translationally acetylated lysine to coenzyme A (CoA), to yield acetyl-CoA, while regenerating the free amine of protein lysine residues. We validate these findings by in vitro biochemical assays using recombinantly purified human ABHD14B in conjunction with cellular studies in a mammalian cell line by knocking down ABHD14B and by identification of a putative substrate binding site. Finally, we report the development and characterization of a much-needed, exquisitely selective ABHD14B antibody, and using it, we map the cellular and tissue distribution of ABHD14B and prospective metabolic pathways that this enzyme might biologically regulate.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.9b00703.

    • Figures S1–S5 (PDF)

    Accession Codes

    The Uniprot IDs for human and mouse ABHD14B are Q96IU4 and Q8VCR7, respectively. The PDB entry for WT human ABHD14B is 1IMJ. (23)

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    Cited By

    This article is cited by 10 publications.

    1. Kundan Kumar, Amol Mhetre, Girish S. Ratnaparkhi, Siddhesh S. Kamat. A Superfamily-wide Activity Atlas of Serine Hydrolases in Drosophila melanogaster. Biochemistry 2021, 60 (16) , 1312-1324. https://doi.org/10.1021/acs.biochem.1c00171
    2. Shubham Singh, Alaumy Joshi, Siddhesh S. Kamat. Mapping the Neuroanatomy of ABHD16A, ABHD12, and Lysophosphatidylserines Provides New Insights into the Pathophysiology of the Human Neurological Disorder PHARC. Biochemistry 2020, 59 (24) , 2299-2311. https://doi.org/10.1021/acs.biochem.0c00349
    3. Kaveri Vaidya, Golding Rodrigues, Sonali Gupta, Archit Devarajan, Mihika Yeolekar, M. S. Madhusudhan, Siddhesh S. Kamat. Identification of sequence determinants for the ABHD14 enzymes. Proteins: Structure, Function, and Bioinformatics 2023, 75 https://doi.org/10.1002/prot.26632
    4. Brittney Racioppo, Nan Qiu, Alexander Adibekian. Serine Hydrolase Activity‐Based Probes for Use in Chemical Proteomics. Israel Journal of Chemistry 2023, 63 (3-4) https://doi.org/10.1002/ijch.202300016
    5. Aron S Buchman, Lei Yu, Hans-Ulrich Klein, Andrea R Zammit, Shahram Oveisgharan, Francine Grodstein, Shinya Tasaki, Allan I Levey, Nicholas T Seyfried, David A Bennett, . Proteome-Wide Discovery of Cortical Proteins That May Provide Motor Resilience to Offset the Negative Effects of Pathologies in Older Adults. The Journals of Gerontology: Series A 2023, 78 (3) , 494-503. https://doi.org/10.1093/gerona/glac105
    6. D. N. Kashirina, L. Kh. Pastushkova, A. G. Brzhozovskiy, A. S. Kononikhin, V. B. Rusanov, V. Yu. Kukanov, O. V. Popova, M. G. Tyuzhin, E. N. Nikolaev, I. M. Larina, O. I. Orlov. A Study on the Protein Composition of Dry Blood Spots of Healthy Volunteers in an Experiment with Hypomagnetic Conditions. Human Physiology 2023, 49 (1) , 77-87. https://doi.org/10.1134/S0362119722600369
    7. Abinaya Rajendran, Amarendranath Soory, Neha Khandelwal, Girish Ratnaparkhi, Siddhesh S. Kamat. A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals. Journal of Biological Chemistry 2022, 298 (7) , 102128. https://doi.org/10.1016/j.jbc.2022.102128
    8. Shubham Singh, Siddhesh S. Kamat. The loss of enzymatic activity of the PHARC‐associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation. European Journal of Neuroscience 2021, 54 (10) , 7442-7457. https://doi.org/10.1111/ejn.15516
    9. Neha Khandelwal, Minhaj Shaikh, Amol Mhetre, Shubham Singh, Theja Sajeevan, Alaumy Joshi, Kithiganahalli Narayanaswamy Balaji, Harinath Chakrapani, Siddhesh S. Kamat. Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs. Cell Chemical Biology 2021, 28 (8) , 1169-1179.e6. https://doi.org/10.1016/j.chembiol.2021.01.008
    10. Mario Navarrete, Brice Korkmaz, Carla Guarino, Adam Lesner, Ying Lao, Julie Ho, Peter Nickerson, John A. Wilkins. Activity-based protein profiling guided identification of urine proteinase 3 activity in subclinical rejection after renal transplantation. Clinical Proteomics 2020, 17 (1) https://doi.org/10.1186/s12014-020-09284-9

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