Negative Feedbacks by Isoprenoids on a Mevalonate Kinase Expressed in the Corpora Allata of Mosquitoes

Abstract

BackgroundJuvenile hormones (JH) regulate development and reproductive maturation in insects. JHs are synthesized through the mevalonate pathway (MVAP), an ancient metabolic pathway present in the three domains of life. Mevalonate kinase (MVK) is a key enzyme in the MVAP. MVK catalyzes the synthesis of phosphomevalonate (PM) by transferring the γ-phosphoryl group from ATP to the C5 hydroxyl oxygen of mevalonic acid (MA). Despite the importance of MVKs, these enzymes have been poorly characterized in insects.ResultsWe functionally characterized an Aedes aegypti MVK (AaMVK) expressed in the corpora allata (CA) of the mosquito. AaMVK displayed its activity in the presence of metal cofactors. Different nucleotides were used by AaMVK as phosphoryl donors. In the presence of Mg2+, the enzyme has higher affinity for MA than ATP. The activity of AaMVK was regulated by feedback inhibition from long-chain isoprenoids, such as geranyl diphosphate (GPP) and farnesyl diphosphate (FPP).Conclusions AaMVK exhibited efficient inhibition by GPP and FPP (Ki less than 1 μM), and none by isopentenyl pyrophosphate (IPP) and dimethyl allyl pyrophosphate (DPPM). These results suggest that GPP and FPP might act as physiological inhibitors in the synthesis of isoprenoids in the CA of mosquitoes. Changing MVK activity can alter the flux of precursors and therefore regulate juvenile hormone biosynthesis.

Analysis of OeMVK Gene Expression in Different Olive Tissues Using Real Time PCR

“…OeMVK 3D model showed similar fashion in other MVK proteins ( Fig. 2a) [2,3]. A conserved glycine-rich sequence "GSGLGSSA" which forms a phosphate-binding loop in all GHMP kinases, a conserved amino acid sequence "KLTGAGGGGC" that stabilizes the phosphate binding loop and a conserved motif contains "KIILAGEHA" PTS2 motif which is consisted of a part of the active site at similar positions as in Arabidopsis thaliana Mevalonate Kinase (NM_180753 ) and other plant MVK proteins [3].…”

Identification and characterization of genes involving the early step of Juvenile Hormone pathway in Helicoverpa armigera

“…In A. aegypti , FPPase efficiently hydrolyzed FPP into farnesol, and silencing of AaFPPase-1 caused a significant decrease in JH biosynthesis, which strengthened the possibility that FPP acted as the crucial enzyme in regulating JH synthesis 22 . Similarly, the activity of A. aegypti Mk exhibited efficient feedback inhibition from long-chain isoprenoids, such as geranyl diphosphate and farnesyl diphosphate 61 . This study also showed that knockdown of Fpps 4 caused a significant decline in JH titer, leading to the darkening of cuticle and the molting disturbance in larvae (Fig.…”

Diterpenes and their derivatives as promising agents against dengue virus and dengue vectors: A literature‐based review

“…These results suggest that GDP might act as a physiological inhibitor in the synthesis of isoprenoids in the Corpora Allata of mosquitoes. In addition, research findings indicated that changing MVK activity can alter the flux of precursors and therefore regulate juvenile hormone biosynthesis (Nyati, Rivera‐Perez, & Noriega, ). Data presented in Table include diterpenoids with promising antiviral effects, including andrographolide, among others.…”

“…Due to their lesser side effects and cost, therapies such as natural products, have attracted the attention of the scientific and medical communities as options to treat and manage DENV infections. Terpenes, a large and diverse class of Test system(s) Activity (possible mechanism(s)) References (Nyati, Rivera-Perez, & Noriega, 2015). Data presented in Table 1 include diterpenoids with promising antiviral effects, including andrographolide, among others.…”