An epigenetic modifier induces production of (10′S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla

Juliana R. Gubiani, E. M Kithsiri Wijeratne, Taoda Shi, Angela R. Araujo, A. Elizabeth Arnold, Eli Chapman, A. A Leslie Gunatilaka

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Abstract

Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10′S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3′,4′-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher's ester method. The absolute structure of (10′S)-verruculide B was determined as 5-[(10′S,2′E,6′E)-10′,11′-dihydroxy-3′,7′,11′-trimethyldodeca-2′,6′-dien-1′-yl]-(3R)-6,8-dihydroxy-3-methylisochroman-1-one (1) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T-cell PTP (TCPTP) with IC50 values of 13.7 ± 3.4, 8.8 ± 0.6, and 16.6 ± 3.8 μM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed.

LanguageEnglish (US)
Pages1860-1866
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number6
DOIs
StatePublished - Mar 15 2017

Fingerprint

Endophytes
Protein Tyrosine Phosphatases
Epigenomics
verruculide B
Metabolites
Non-Receptor Type 2 Protein Tyrosine Phosphatase
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Protein Phosphatase 1
Histone Deacetylase Inhibitors
Esters
Fungi
T-Lymphocytes
vorinostat
vermistatin
protein phosphatase-T
nafuredin
E 10
T-cells

Keywords

  • (10′S)-verruculide B
  • Epigenetic
  • Histone deacetylase inhibitor
  • Phoma sp. nov. LG0217
  • Protein tyrosine phosphatases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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title = "An epigenetic modifier induces production of (10′S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla",
abstract = "Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10′S)-verruculide B (1), vermistatin (2) and dihydrovermistatin (3). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, (S,Z)-5-(3′,4′-dihydroxybutyldiene)-3-propylfuran-2(5H)-one (4) together with nafuredin (5). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher's ester method. The absolute structure of (10′S)-verruculide B was determined as 5-[(10′S,2′E,6′E)-10′,11′-dihydroxy-3′,7′,11′-trimethyldodeca-2′,6′-dien-1′-yl]-(3R)-6,8-dihydroxy-3-methylisochroman-1-one (1) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T-cell PTP (TCPTP) with IC50 values of 13.7 ± 3.4, 8.8 ± 0.6, and 16.6 ± 3.8 μM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed.",
keywords = "(10′S)-verruculide B, Epigenetic, Histone deacetylase inhibitor, Phoma sp. nov. LG0217, Protein tyrosine phosphatases",
author = "Gubiani, {Juliana R.} and Wijeratne, {E. M Kithsiri} and Taoda Shi and Araujo, {Angela R.} and Arnold, {A. Elizabeth} and Eli Chapman and Gunatilaka, {A. A Leslie}",
year = "2017",
month = "3",
doi = "10.1016/j.bmc.2017.01.048",
volume = "25",
pages = "1860--1866",
journal = "Bioorganic and Medicinal Chemistry",
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T1 - An epigenetic modifier induces production of (10′S)-verruculide B, an inhibitor of protein tyrosine phosphatases by Phoma sp. nov. LG0217, a fungal endophyte of Parkinsonia microphylla

AU - Gubiani,Juliana R.

AU - Wijeratne,E. M Kithsiri

AU - Shi,Taoda

AU - Araujo,Angela R.

AU - Arnold,A. Elizabeth

AU - Chapman,Eli

AU - Gunatilaka,A. A Leslie

PY - 2017/3/15

Y1 - 2017/3/15

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