Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Int J Biol Macromol. 2024 May;267(Pt 2):131510. doi: 
10.1016/j.ijbiomac.2024.131510. Epub 2024 Apr 10.

Natural product guvermectin inhibits guanosine 5'-monophosphate synthetase and 
confers broad-spectrum antibacterial activity.

Zhang M(1), Li L(2), Li C(3), Ma A(4), Li J(5), Yang C(6), Chen X(7), Cao P(8), 
Li S(6), Zhang Y(6), Yuchi Z(9), Du X(7), Liu C(2), Wang X(2), Wang X(10), Xiang 
W(11).

Author information:
(1)State Key Laboratory for Biology of Plant Diseases and Insect Pests, 
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 
100193, China; Department of Entomology and MOA Key Lab of Pest Monitoring and 
Green Management, Plant Pathology Department, College of Plant Protection, China 
Agricultural University, Beijing 100193, China.
(2)Key Laboratory of Agricultural Microbiology of Heilongjiang Province, 
Northeast Agricultural University, Harbin 150030, China.
(3)College of Agriculture, Key Laboratory of Agricultural Microbiology of 
Guizhou Province, Guizhou University, Guiyang 550025, China.
(4)State Key Laboratory of Plant Physiology and Biochemistry, College of 
Biological Sciences, China Agricultural University, Beijing 100193, China.
(5)Key Laboratory of Microbial Resources Collection and Preservation, Ministry 
of Agriculture and Rural Affairs, Institute of Agricultural Resources and 
Regional Planning, Chinese Academy of Agricultural Sciences, Beijing 100081, 
China.
(6)State Key Laboratory for Biology of Plant Diseases and Insect Pests, 
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 
100193, China.
(7)Department of Entomology and MOA Key Lab of Pest Monitoring and Green 
Management, Plant Pathology Department, College of Plant Protection, China 
Agricultural University, Beijing 100193, China.
(8)Key Laboratory of Drug Targets and Drug Leads for Degenerative Diseases, 
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, 
Nanjing University of Chinese Medicine, Nanjing 210023, China.
(9)Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, 
Collaborative Innovation Center of Chemical Science and Engineering, School of 
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, 
China.
(10)Department of Entomology and MOA Key Lab of Pest Monitoring and Green 
Management, Plant Pathology Department, College of Plant Protection, China 
Agricultural University, Beijing 100193, China. Electronic address: 
xdwang@cau.edu.cn.
(11)State Key Laboratory for Biology of Plant Diseases and Insect Pests, 
Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 
100193, China; Key Laboratory of Agricultural Microbiology of Heilongjiang 
Province, Northeast Agricultural University, Harbin 150030, China. Electronic 
address: xiangwensheng@neau.edu.cn.

Bacterial diseases caused substantial yield losses worldwide, with the rise of 
antibiotic resistance, there is a critical need for alternative antibacterial 
compounds. Natural products (NPs) from microorganisms have emerged as promising 
candidates due to their potential as cost-effective and environmentally friendly 
bactericides. However, the precise mechanisms underlying the antibacterial 
activity of many NPs, including Guvermectin (GV), remain poorly understood. 
Here, we sought to explore how GV interacts with Guanosine 5'-monophosphate 
synthetase (GMPs), an enzyme crucial in bacterial guanine synthesis. We employed 
a combination of biochemical and genetic approaches, enzyme activity assays, 
site-directed mutagenesis, bio-layer interferometry, and molecular docking 
assays to assess GV's antibacterial activity and its mechanism targeting GMPs. 
The results showed that GV effectively inhibits GMPs, disrupting bacterial 
guanine synthesis. This was confirmed through drug-resistant assays and direct 
enzyme inhibition studies. Bio-layer interferometry assays demonstrated specific 
binding of GV to GMPs, with dependency on Xanthosine 5'-monophosphate. 
Site-directed mutagenesis identified key residues crucial for the GV-GMP 
interaction. This study elucidates the antibacterial mechanism of GV, 
highlighting its potential as a biocontrol agent in agriculture. These findings 
contribute to the development of novel antibacterial agents and underscore the 
importance of exploring natural products for agricultural disease management.

Copyright © 2024 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ijbiomac.2024.131510
PMID: 38608989 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors 
declare that they have no known competing financial interests or personal 
relationships that could have appeared to influence the work reported in this 
paper.


2. Protein Sci. 2023 Aug;32(8):e4703. doi: 10.1002/pro.4703.

Insight into the role of the Bateman domain at the molecular and physiological 
levels through engineered IMP dehydrogenases.

Gedeon A(1), Ayoub N(1), Brûlé S(2), Raynal B(2), Karimova G(3), Gelin M(4), 
Mechaly A(5), Haouz A(5), Labesse G(4), Munier-Lehmann H(1).

Author information:
(1)Institut Pasteur, Université Paris Cité, Unité de Chimie et Biocatalyse, CNRS 
UMR3523, Paris, France.
(2)Institut Pasteur, Université Paris Cité, Plate-Forme de Biophysique 
Moléculaire, C2RT, CNRS UMR3528, Paris, France.
(3)Institut Pasteur, Université Paris Cité, Unité de Biochimie des Interactions 
Macromoléculaires, CNRS UMR3528, Paris, France.
(4)Centre de Biologie Structurale, Université Montpellier, INSERM, CNRS, 
Montpellier, France.
(5)Institut Pasteur, Université Paris Cité, Plate-Forme de Cristallographie, 
C2RT, CNRS UMR3528, Paris, France.

Inosine 5'-monophosphate (IMP) dehydrogenase (IMPDH) is an ubiquitous enzyme 
that catalyzes the NAD+ -dependent oxidation of inosine 5'-monophosphate into 
xanthosine 5'-monophosphate. This enzyme is formed of two distinct domains, a 
core domain where the catalytic reaction occurs, and a less-conserved Bateman 
domain. Our previous studies gave rise to the classification of bacterial IMPDHs 
into two classes, according to their oligomeric and kinetic properties. MgATP is 
a common effector but cause to different effects when it binds within the 
Bateman domain: it is either an allosteric activator for Class I IMPDHs or a 
modulator of the oligomeric state for Class II IMPDHs. To get insight into the 
role of the Bateman domain in the dissimilar properties of the two classes, 
deleted variants of the Bateman domain and chimeras issued from the interchange 
of the Bateman domain between the three selected IMPDHs have been generated and 
characterized using an integrative structural biology approach. Biochemical, 
biophysical, structural, and physiological studies of these variants unveil the 
Bateman domain as being the carrier of the molecular behaviors of both classes.

© 2023 The Protein Society.

DOI: 10.1002/pro.4703
PMCID: PMC10357500
PMID: 37338125 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing financial 
interests.


3. Biochemistry. 2022 Sep 20;61(18):1988-2006. doi: 10.1021/acs.biochem.2c00151. 
Epub 2022 Aug 30.

Mechanistic Insights into the Functioning of a Two-Subunit GMP Synthetase, an 
Allosterically Regulated, Ammonia Channeling Enzyme.

Shivakumaraswamy S(1), Kumar S(1), Bellur A(1), Polisetty SD(1), Balaram H(1).

Author information:
(1)Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
Scientific Research, Jakkur, Bengaluru 560064, India.

Guanosine 5'-monophosphate (GMP) synthetases, enzymes that catalyze the 
conversion of xanthosine 5'-monophosphate (XMP) to GMP, are composed of two 
different catalytic units, which are either two domains of a polypeptide chain 
or two subunits that associate to form a complex. The glutamine amidotransferase 
(GATase) unit hydrolyzes glutamine generating ammonia, and the ATP 
pyrophosphatase (ATPPase) unit catalyzes the formation of an AMP-XMP 
intermediate. The substrate-bound ATPPase allosterically activates GATase, and 
the ammonia thus generated is tunneled to the ATPPase active site where it 
reacts with AMP-XMP generating GMP. In ammonia channeling enzymes reported thus 
far, a tight complex of the two subunits is observed, while the interaction of 
the two subunits of Methanocaldococcus jannaschii GMP synthetase (MjGMPS) is 
transient with the underlying mechanism of allostery and substrate channeling 
largely unclear. Here, we present a mechanistic model encompassing the various 
steps in the catalytic cycle of MjGMPS based on biochemical experiments, crystal 
structure, and cross-linking mass spectrometry guided integrative modeling. pH 
dependence of enzyme kinetics establishes that ammonia is tunneled across the 
subunits with the lifetime of the complex being ≤0.5 s. The crystal structure of 
the XMP-bound ATPPase subunit reported herein highlights the role of 
conformationally dynamic loops in enabling catalysis. The structure of MjGMPS 
derived using restraints obtained from cross-linking mass spectrometry has 
enabled the visualization of subunit interactions that enable allostery under 
catalytic conditions. We integrate the results and propose a functional 
mechanism for MjGMPS detailing the various steps involved in catalysis.

DOI: 10.1021/acs.biochem.2c00151
PMID: 36040251 [Indexed for MEDLINE]


4. J Pharm Biomed Anal. 2022 Sep 20;219:114886. doi: 10.1016/j.jpba.2022.114886. 
Epub 2022 Jun 11.

Quantitative analysis of 20 purine and pyrimidine metabolites by HILIC-MS/MS in 
the serum and hippocampus of depressed mice.

Lu Z(1), Li S(2), Aa N(3), Zhang Y(1), Zhang R(1), Xu C(1), Zhang S(1), Kong 
X(3), Wang G(1), Aa J(4), Zhang Y(5).

Author information:
(1)Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, 
China Pharmaceutical University, Nanjing 210009, China.
(2)Department of Pharmacy, The First Affiliated Hospital of Soochow University, 
Suzhou 215006, China.
(3)Department of Cardiology, The First Affiliated Hospital of Nanjing Medical 
University, Nanjing 210009, China.
(4)Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, 
China Pharmaceutical University, Nanjing 210009, China. Electronic address: 
jiyea@cpu.edu.cn.
(5)Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, 
China Pharmaceutical University, Nanjing 210009, China. Electronic address: 
1520200017@cpu.edu.cn.

Purine and pyrimidine metabolism are vital metabolic pathways in the 
development, proliferation or repairment of cells or tissues associated with 
various diseases. Here, a simple, all-in-one injection hydrophilic interaction 
liquid chromatography-tandem mass spectrometry method was developed for 
simultaneous determination of 20 metabolites: adenine, adenosine, 
deoxyadenosine, adenosine 5'-monophosphate, cyclic adenosine monophosphate, 
hypoxanthine, xanthine, inosine, deoxyinosine, xanthosine, xanthosine 
5'-monophosphate and uric acid, which are products of purine metabolism; 
uridine, deoxyuridine, uridine 5'-monophosphate and uracil, are products of 
pyrimidine metabolism; and corticosterone, methionine, acetylcholine and 
serotonin. To minimize interference of endogenous molecules in sample matrixes, 
a combination of activated carbon adsorption and a serum substitute matrix (5% 
bovine serum albumin in phosphate buffered saline) was utilized and jointly 
applied. The sensitivity, linearity, stability, precision, accuracy and 
extraction recovery were evaluated, and the method was demonstrated to be 
accurate, sensitive and reliable. An analytical strategy was successfully 
applied to quantitatively determine 20 metabolite levels in the serum and 
hippocampus of mice with chronic social defeat stress-induced depression. The 
results showed greatly perturbed purine metabolism in the depressed mice, which 
was primarily characterized by dramatic increases in hypoxanthine, xanthine and 
inosine in serum and reduced levels of adenine, adenosine and adenosine 
5'-monophosphate in the hippocampus. These findings suggest that this novel 
strategy can facilitate the quantitative analysis of adenine and other purine 
and pyrimidine metabolites in tissue and serum and exhibits great potential in 
the exploration of metabolism-related mechanisms of relevant diseases.

Copyright © 2022. Published by Elsevier B.V.

DOI: 10.1016/j.jpba.2022.114886
PMID: 35715372 [Indexed for MEDLINE]


5. Transplantation. 2021 Apr 1;105(4):916-927. doi: 10.1097/TP.0000000000003336.

Inosine 5'-Monophosphate Dehydrogenase Activity for the Longitudinal Monitoring 
of Mycophenolic Acid Treatment in Kidney Allograft Recipients.

Glander P(1), Waiser J(1), Hambach P(1), Bachmann F(1), Budde K(1), Eckardt 
KU(1), Friedersdorff F(2), Gaedeke J(1), Kron S(1), Lorkowski C(1), Mai M(1), 
Neumayer HH(1), Peters R(2), Rudolph B(3), Schmidt D(4), Wu K(3), Liefeldt L(1).

Author information:
(1)Department of Nephrology and Internal Intensive Care Medicine, Charité - 
Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
(2)Department of Urology, Charité - Universitätsmedizin Berlin, Campus Charité 
Mitte, Berlin, Germany.
(3)Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, 
Germany.
(4)Business Unit IT, Charité - Universitätsmedizin Berlin, Berlin, Germany.

BACKGROUND: Mycophenolic acid (MPA) is a standard immunosuppressant in organ 
transplantation. A simple monitoring biomarker for MPA treatment has not been 
established so far. Here, we describe inosine 5'-monophosphate dehydrogenase 
(IMPDH) monitoring in erythrocytes and its application to kidney allograft 
recipients.
METHODS: IMPDH activity measurements were performed using a high-performance 
liquid chromatography assay. Based on 4203 IMPDH measurements from 1021 
patients, we retrospectively explored the dynamics early after treatment start. 
In addition, we analyzed the influence of clinically relevant variables on IMPDH 
activity in a multivariate model using data from 711 stable patients. 
Associations between IMPDH activity and clinical events were evaluated in 
hospitalized patients.
RESULTS: We found that IMPDH activity reflects MPA exposure after 8 weeks of 
constant dosing. In addition to dosage, body mass index, renal function, and 
coimmunosuppression affected IMPDH activity. Significantly lower IMPDH 
activities were found in patients with biopsy-proven acute rejection as compared 
to patients without rejection (median [interquartile range]: 696 [358-1484] 
versus 1265 [867-1618] pmol xanthosine-5'-monophosphate/h/mg hemoglobin, 
P < 0.001). The highest IMPDH activities were observed in hospitalized patients 
with clinically evident MPA toxicity as compared to patients with 
hospitalization not related to MPA treatment (1548 [1021-2270] versus 1072 
[707-1439] pmol xanthosine-5'-monophosphate/h/mg hemoglobin; P < 0.001). 
Receiver operating characteristic curve analyses underlined the usefulness of 
IMPDH to predict rejection episodes (area, 0.662; confidence interval, 
0.584-0.740; P < 0.001) and MPA-associated adverse events (area, 0.632; 
confidence interval, 0.581-0.683; P < 0.001), respectively.
CONCLUSIONS: IMPDH measurement in erythrocytes is a novel and useful strategy 
for the longitudinal monitoring of MPA treatment.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

DOI: 10.1097/TP.0000000000003336
PMID: 32496356 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no funding or conflicts of 
interest.