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Inhibition of methionine adenosyltransferase by the polyamines
A M Geller1, H L Legros, K Wherry
1Department of Biochemistry, The University of Tennessee, Memphis, Tennessee 38163, USA. ageller@physio1.utmem.edu
Abstract:
The effect of the polyamines, putrescine, spermine, and spermidine, on the activity of extrahepatic methionine adenosyltransferase (MAT II) was studied. The polyamines inhibited MAT II activity at concentrations equal to or greater than 5 mm. Combinations of polyamines were more effective than individual polyamines in inhibiting MAT activity; maximum inhibition approached 80% with combinations of all three polyamines. S-Adenosylmethionine (AdoMet), Pi, and PPi, the products of the MAT reaction, are known to be synergistic inhibitors of the nonhepatic form of the enzyme. Combinations of polyamines plus Pi and/or PPi induced an additive inhibition of the enzyme. AdoMet plus polyamines also resulted in significant inhibition, but inhibition plateaued at about 80%, indicating the presence of a protective mechanism to maintain AdoMet synthesis. Extrahepatic MAT from human and rat tissues was inhibited by the polyamines, indicating that this phenomenon is not species specific. In addition, we examined the effect of polyamines on MAT activity in resting and activated human lymphocytes that were shown to differ in the relative expression of MAT II subunits. Although MAT from mitogen (phytohemagglutinin, PHA)- and superantigen (Staphylococcal enterotoxin B, SEB)-stimulated lymphocytes were similarly inhibited by 10 mM polyamines, at lower concentrations of polyamines (1-5 mM), MAT from SEB-stimulated cells appeared to be more susceptible to inhibition by the polyamines. Inasmuch as SEB is a more physiological stimulator of T cells than PHA, the data suggest a possible role of polyamines in regulating MAT activity.
Insights
Polyamines like putrescine, spermine, and spermidine inhibit extrahepatic methionine adenosyltransferase (MAT II) activity. Combinations of polyamines and reaction products further regulate MAT II, suggesting a role in controlling methionine metabolism.
Area of Science:
- Biochemistry
- Enzymology
- Cell Biology
Background:
- Methionine adenosyltransferase (MAT) is crucial for synthesizing S-Adenosylmethionine (AdoMet).
- Extrahepatic MAT (MAT II) activity is regulated by various factors.
- Polyamines are essential for cell growth and proliferation.
Purpose of the Study:
- To investigate the effect of polyamines on extrahepatic MAT II activity.
- To determine if polyamines interact with known MAT II inhibitors.
- To explore the role of polyamines in regulating MAT II in activated lymphocytes.
Main Methods:
- Enzyme activity assays using purified extrahepatic MAT II.
- Testing inhibition by individual and combined polyamines (putrescine, spermine, spermidine).
- Assessing combined inhibition with reaction products (AdoMet, Pi, PPi) and in stimulated lymphocytes.
Main Results:
- Polyamines inhibited MAT II activity at concentrations ≥ 5 mM, with combinations showing greater effect (up to 80% inhibition).
- Polyamines exhibited additive inhibition with Pi and PPi, and synergistic inhibition with AdoMet, though AdoMet synthesis was protected.
- MAT II from human and rat tissues was similarly inhibited, and MAT from SEB-stimulated lymphocytes was more sensitive to lower polyamine concentrations.
Conclusions:
- Polyamines are potent inhibitors of extrahepatic MAT II.
- A regulatory mechanism exists to maintain AdoMet synthesis despite polyamine inhibition.
- Polyamines may play a role in regulating MAT activity in activated immune cells, particularly under physiological stimulation.