Review
Oncology
Molly E. Muehlebach, Sarah A. Holstein
Summary: Geranylgeranyl diphosphate synthase (GGDPS) is an enzyme that synthesizes Geranylgeranyl pyrophosphate (GGPP), a substrate for post-translational modification of proteins in the Ras superfamily. Abnormal expression of GGDPS has been implicated in various human pathologies. This review discusses the physiological function of GGDPS, its role in pathophysiological processes, and the therapeutic implications of targeting this enzyme.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Agriculture, Multidisciplinary
Junhua Wang, Linghuan Zhu, Youran Li, Sha Xu, Wei Jiang, Chaojuan Liang, Yakun Fang, Alex Chu, Liang Zhang, Zhongyang Ding, Guiyang Shi
Summary: By using a GGPP synthase with stronger catalytic ability and increasing the metabolic flux of the MVA pathway and the supply of IPP, the production of GGOH in Saccharomyces cerevisiae was significantly enhanced. These strategies can also be applied to enhance the production of other terpenoids in the future.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2021)
Article
Biochemical Research Methods
Wayne Zita, Venkatasalam Shanmugabalaji, Miguel Ezquerro, Manuel Rodriguez-Concepcion, Felix Kessler, Gaetan Glauser
Summary: In this study, a method was developed to quantify GGPP and GGP in tomato fruit using UHPLC-MS/MS. The validity of the method was confirmed by analyzing GGPP contents in wild-type tomatoes and mutants defective in GGPP production. Sample preparation was also shown to be crucial in preventing GGPP hydrolysis and minimizing its conversion to GGP.
Editorial Material
Oncology
Kobina Essandoh, Richard J. Auchus, Matthew J. Brody
Summary: The study demonstrates the importance of local isoprenoid synthesis in cardiac homeostasis, with FPPS deficiency leading to increased prenylation of Ras and Rheb, resulting in dilated cardiomyopathy and activation of ERK1/2 and mTOR signaling pathways. Inhibition of farnesyltransferase can ameliorate cardiomyopathy and pathway activation caused by loss of FPPS.
JOURNAL OF PATHOLOGY
(2022)
Article
Pharmacology & Pharmacy
Staci L. Haney, Michelle L. Varney, Yashpal Chhonker, Geoffrey Talmon, Lynette M. Smith, Daryl J. Murry, Sarah A. Holstein
Summary: Combination therapy with GGSI and statins demonstrates potential anti-tumor effects in mice, particularly for multiple myeloma. In vivo experiments show the ability to disrupt protein geranylgeranylation and slow tumor growth.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Plant Sciences
M. Victoria Barja, Miguel Ezquerro, Stefano Beretta, Gianfranco Diretto, Igor Florez-Sarasa, Elisenda Feixes, Alessia Fiore, Rumyana Karlova, Alisdair R. Fernie, Jules Beekwilder, Manuel Rodriguez-Concepcion
Summary: GGPPS family members in tomato's plastids interact with PSY isoforms, with SlG2 physically interacting with PSY proteins. CRISPR-Cas9 mutants showed that defects in SlG3 have a greater impact on carotenoid levels and derived phenotypes compared to defects in SlG2.
Article
Biochemistry & Molecular Biology
Yihua Ma, Qingwen Chen, Yaoyao Wang, Fengxia Zhang, Chengyuan Wang, Guodong Wang
Summary: This study provides genetic evidence that GFPPS is responsible for the production of C25 terpenes in Arabidopsis. Blocking the sesterterpene pathway at the GFPPS step increases the production of GGPP-derived terpenes. The study also reveals that GFPPS directly decreases the activity of GGPPS through protein-protein interaction, leading to GGPP deficiency in planta.
JOURNAL OF INTEGRATIVE PLANT BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alisa E. R. Fairweather, Daniel B. Goetz, Chloe M. Schroeder, Nazmul H. Bhuiyan, Michelle L. Varney, David F. Wiemer, Sarah A. Holstein
Summary: This study investigated the structure-function relationship of a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors through preparation and evaluation of novel alpha-modified triazole phosphonates. The flexibility at the alpha position of the bisphosphonate derivatives was found to accommodate a variety of substituents without affecting potency, while the monophosphonate derivatives lacked activity. The findings lay the foundation for future studies on the impact of alpha-modifications on in vivo activity of GGDPS inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Stephanie Kabeche, Jumpei Aida, Thamina Akther, Takashi Ichikawa, Atsuko Ochida, Michael J. Pulkoski-Gross, Mark Smith, Paul S. Humphries, Ellen Yeh
Summary: A series of novel thiazole-containing amides were synthesized and studied for their structure-activity relationship, leading to the identification of potent and selective PfFPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were advanced to mouse in vivo PK studies, showing adequate free drug exposure for further investigation.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Physical
Baofu Xu, Zining Li, Tyler A. Alsup, Michelle A. Ehrenberger, Jeffrey D. Rudolf
Summary: This study reveals the ability of terpene synthases to catalyze prenylation on small molecules, supports its physiological relevance in vivo, and proposes a substrate decoy mechanism.
Review
Chemistry, Multidisciplinary
Jacque L. Faylo, Trey A. Ronnebaum, David W. Christianson
Summary: The chemodiversity of terpenoid natural products is largely attributed to the catalysis of prenyltransferases and cyclases, which generate complex hydrocarbon compounds through chain elongation reactions. Terpene cyclization reactions are characterized by changes in chemical bonding of substrate carbon atoms, with different classes of cyclases based on the chemistry of carbocation formation.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Chen Dong, Mei Zhang, Shanshan Song, Fang Wei, Lili Qin, Puqing Fan, Yongchun Shi, Xiaoran Wang, Ran Wang
Summary: As an essential antioxidant, carotenoids play a crucial role in the light harvesting for photosynthesis and defense against high light stress in plants. In this study, researchers identified a small subunit (SSU) of geranylgeranyl diphosphate synthase (GGPPS), NtSSU II, in Nicotiana tabacum. NtSSU II forms enzymatic components with NtGGPPS1 and NtPSY1 to regulate carotenoid biosynthesis. The study also found that NtSSU II is distributed in various plant tissues and is influenced by light conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Chen Dong, Zhiwen Wang, Lili Qin, Chen Zhang, Longyun Cao, Haifeng Li, Xintian Ma
Summary: This study identifies the key gene NnGGPPS1 in the traditional Chinese herb Nelumbo nucifera, which plays a vital role in the biosynthesis of carotenoid and chlorophyll. Overexpression of NnGGPPS1 improves the growth and pigment synthesis in transgenic tobacco plants. This finding is of great importance for the research and development of traditional Chinese medicine.
Article
Biochemistry & Molecular Biology
Evangelia Katsavou, Chara Sarafoglou, Vasileia Balabanidou, Evangelia Skoufa, Ralf Nauen, Marc Linka, Sven Geibel, Shane Denecke, John Vontas
Summary: Geranylgeranyl pyrophosphate synthase (GGPPS) plays a crucial role in insect physiological processes. The study investigated GGPPS in Spodoptera frugiperda and Helicoverpa armigera, and developed an enzyme assay to identify potential inhibitors.
INSECT MOLECULAR BIOLOGY
(2023)
Article
Plant Sciences
Miguel Ezquerro, Changsheng Li, Julia Perez-Perez, Esteban Burbano-Erazo, M. Victoria Barja, Yanting Wang, Lemeng Dong, Purificacion Lison, M. Pilar Lopez-Gresa, Harro J. Bouwmeester, Manuel Rodriguez-Concepcion
Summary: This study investigated the function of SlG1, a gene involved in carotenoid and strigolactone (SL) synthesis. The results showed that slg1 lines displayed a wild-type phenotype under normal growth conditions. However, under bacterial infection, slg1 leaves produced lower levels of defensive diterpenoids. In roots, SlG1 co-expressed with PSY3 and was involved in SL production, but did not affect shoot branching phenotype.