| Reference | 1. Chem Sci. 2018 Jan 24;9(9):2589-2594. doi: 10.1039/c7sc02396k. eCollection 2018
Mar 7.
<br>
Asperphenamate biosynthesis reveals a novel two-module NRPS system to synthesize
amino acid esters in fungi.
<br>
Li W(1)(2)(3), Fan A(1), Wang L(1), Zhang P(1), Liu Z(1), An Z(4), Yin
WB(1)(2)(3).
<br>
Author information:
<br>
(1)State Key Laboratory of Mycology , Institute of Microbiology , Chinese Academy
of Sciences , 100101 Beijing , China . Email: [email protected].
(2)Savaid Medical School , University of Chinese Academy of Sciences , Beijing ,
100049 , China.
(3)State Key Laboratory of Bioactive Substance and Function of Natural Medicines
, Institute of Materia Medica , Chinese Academy of Medical Sciences and Peking
Union Medical College , Beijing , 100050 , China.
(4)Texas Therapeutics Institute , The Brown Foundation Institute of Molecular
Medicine , University of Texas Health Science Center at Houston , Houston , Texas
77030 , USA.
<br>
Amino acid esters are a group of structurally diverse natural products with
distinct activities. Some are synthesized through an inter-molecular
esterification step catalysed by nonribosomal peptide synthetase (NRPS). In
bacteria, the formation of the intra-molecular ester bond is usually catalysed by
a thioesterase domain of NRPS. However, the mechanism by which fungal NRPSs
perform this process remains unclear. Herein, by targeted gene disruption in
Penicillium brevicompactum and heterologous expression in Aspergillus nidulans,
we show that two NRPSs, ApmA and ApmB, are sufficient for the synthesis of an
amino acid ester, asperphenamate. Using the heterologous expression system, we
identified that ApmA, with a reductase domain, rarely generates dipeptidyl
alcohol. In contrast, ApmB was determined to not only catalyse inter-molecular
ester bond formation but also accept the linear dipeptidyl precursor into the
NRPS chain. The mechanism described here provides an approach for the synthesis
of new small molecules with NRPS as the catalyst. Our study reveals for the first
time a two-module NRPS system for the formation of amino acid esters in nature.
<br>
<br>
2. FEMS Microbiol Lett. 2013 Feb;339(2):77-92. doi: 10.1111/1574-6968.12054. Epub
2012 Dec 27.
<br>
Two new Penicillium species Penicillium buchwaldii and Penicillium spathulatum,
producing the anticancer compound asperphenamate.
<br>
Frisvad JC(1), Houbraken J, Popma S, Samson RA.
<br>
Author information:
<br>
(1)Department of Systems Biology, Center for Microbial Biotechnology, DTU-Biosys,
Technical University of Denmark, Lyngby, Denmark. [email protected]
<br>
Penicillium buchwaldii sp. nov. (type strain CBS 117181(T) = IBT 6005(T) = IMI
30428(T) ) and Penicillium spathulatum sp. nov. (CBS 117192(T) = IBT 22220(T) )
are described as new species based on a polyphasic taxonomic approach. Isolates
of P. buchwaldii typically have terverticillate conidiophores with echinulate
thick-walled conidia and produce the extrolites asperphenamate,
citreoisocoumarin, communesin A and B, asperentin and 5′-hydroxy-asperentin.
Penicillium spathulatum is unique in having restricted colonies on Czapek yeast
agar (CYA) with an olive grey reverse, good growth on CYA supplemented with 5%
NaCl, terverticillate bi- and ter-ramulate conidiophores and consistently
produces the extrolites benzomalvin A and D and asperphenamate. The two new
species belong to Penicillium section Brevicompacta and are phylogenetically
closely related to Penicillium tularense. With exception of Penicillium
fennelliae, asperphenamate is also produced by all other species in section
Brevicompacta (P. tularense, Penicillium brevicompactum, Penicillium
bialowiezense, Penicillium olsonii, Penicillium astrolabium and Penicillium
neocrassum). Both new species have a worldwide distribution. The new species were
mainly isolated from indoor environments and food and feedstuffs. The fact that
asperphenamate has been found in many widely different plants may indicate that
endophytic fungi rather than the plants are the actual producers.
<br>
<br>
3. Toxicol Appl Pharmacol. 2012 Aug 15;263(1):21-31. doi:
10.1016/j.taap.2012.05.018. Epub 2012 Jun 2.
<br>
JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced
autophagy in MCF-7 cells.
<br>
Li Y(1), Luo Q, Yuan L, Miao C, Mu X, Xiao W, Li J, Sun T, Ma E.
<br>
Author information:
<br>
(1)Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang
110016, China.
<br>
N-Benzoyl-O-(N’-(1-benzyloxycarbonyl-4-piperidiylcarbonyl)-D-phenylalanyl)-D-phen
ylalaninol (BBP), a novel synthesized asperphenamate derivative with the
increased solubility, showed growth inhibitory effect on human breast carcinoma
MCF-7 cells in a time- and concentration-dependent manner. The growth inhibitory
effect of BBP was associated with induction of autophagy, which was demonstrated
by the development of acidic vesicular organelles, cleavage of LC3 and
upregulation of Atg4 in BBP-treated MCF-7 cells. Since the application of Atg4
siRNA totally blocked the cleavage of LC3, we demonstrated a central role of Atg4
in BBP-induced autophagy. The further studies showed that BBP increased the
levels of reactive oxygen species (ROS), and pretreatment with NAC effectively
blocked the accumulation of ROS, autophagy and growth inhibition triggered by
BBP. Moreover, BBP induced the activation of JNK, and JNK inhibitor SP600125
reversed autophagy, the increase of Atg4 levels, conversion of LC3 and growth
inhibition induced by BBP. Knockdown of JNK by siRNA efficiently inhibited ROS
production and autophagy, but antioxidant NAC failed to block JNK activation
induced by BBP, indicating that JNK activation may be a upstream signaling of ROS
and should be a core component in BBP-induced autophagic signaling pathway. These
results suggest that BBP produces its growth inhibitory effect through induction
of the autophagic cell death in MCF-7 cells, which is modulated by a
JNK-dependent Atg4 upregulation involving ROS production.
<br>
|
