S-adenosylmethionine in liver health, injury, and cancer

Abstract

S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.

Figures

FIGURE 1

Structure of S-adenosyl-l-methionine (AdoMet), S-adenosyl-l-homocysteine (AdoHcy), and 5′-methylthioadenosine (MTA).

FIGURE 2

Methionine metabolism: transmethylation pathway. Methionine adenosyltransferase (MAT) catalyzes the conversion of methionine and ATP into AdoMet. In transmethylation reactions, AdoMet donates its methyl group to a large variety of acceptor molecules (X) in reactions catalyzed by methyl transferases (MTs). AdoMet-dependent methylation reactions yield AdoHcy as a byproduct. AdoHcy cellular content is regulated by the enzyme AdoHcy hydrolase (AHCY), which reversibly cleaves this molecule into adenosine and homocysteine. Remethylation of homocysteine to form methionine occurs by two enzymes: methionine synthase (MS), which requires normal levels of folate and vitamin B12, and betaine homocysteine methyltransferase (BHMT), which requires betaine, a metabolite of choline. MS-catalyzed homocysteine remethylation requires 5-methyltetrahydrofolate (5-MTHF), which is derived from 5,10-methylenetetrahydrofolate (5,10-MTHF) in a reaction catalyzed by methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted to tetrahydrofolate (THF) as it donates its methyl group and THF is converted to 5,10-MTHF to complete the folate cycle.

FIGURE 3

Methionine metabolism: transsulfuration and hydrogen sulfide synthesis. A: the transsulfuration pathway links AdoMet to cysteine biosynthesis. Here homocysteine is converted to cysteine (the rate-limiting precursor for glutathione) via a two-step enzymatic process catalyzed by cystathionine β-synthase (CBS) and cystathionase (CSE), both requiring vitamin B6. α-Ketobutyrate, the other product of cystathionine cleavage, is further metabolized by the mitochondria through the Kreb's cycle. B: hydrogen sulfide synthesis. Although the classical role of CBS and CSE is to generate cystathionine and cysteine, respectively, these two enzymes catalyze multiple hydrogen sulfide (H2S)-generating reactions using cysteine and homocysteine as substrates. The predominant H2S-generating reactions are shown in red. A third pathway uses aspartate aminotransferase (AST) to yield mercaptopyruvate, which is further converted into H2S in a reaction catalyzed by mercaptopyruvate sulfurtransferase (MST). The function of this pathway is primarily catabolic.

FIGURE 4

Methionine metabolism: polyamine synthesis, methionine salvation pathway, and AdoMet radical reactions. To synthesize polyamines, AdoMet needs first to be decarboxylated, a reaction catalyzed by the enzyme AdoMet decarboxylase (AdoMetDC), to form decarboxylated AdoMet (dcAdoMet). The predominant polyamines in mammalian cells are spermidine (SPD) and spermine (SPM). These polyamines are made by sequential addition of aminopropyl groups from dcAdoMet, yielding 5′-methylthioadenosine (MTA) as a byproduct. SPD synthase (SPDS) catalyzes the transfer of the first aminopropyl group from dcAdoMet to putrescine to form SPD and MTA, whereas SPM synthase (SPMS) catalyzes the transfer of the second aminopropyl group to SPD to form SPM and a second molecule of MTA. MTA is metabolized through the methionine salvation pathway to regenerate AdoMet. The first reaction in this pathway is the cleavage of MTA by the enzyme MTA phosphorylase (MTAP) yielding adenine and 5-methylthioribose-1-phosphate, which is further metabolized to methionine and adenine to AMP. AdoMet may be also converted to 5′-deoxyadenosyl 5′-radical by a large family of AdoMet radical enzymes (ARE) and initiate a variety of radical chemical reactions. These enzymes share a CX3CX2C motif forming a characteristic [4Fe-4S] cluster. This [4Fe-4S] cluster binds AdoMet catalyzing its reductive cleavage to generate [4Fe-4S]-methionine and a 5′-deoxyadenosyl 5′-radical. ODC, ornithine decarboxylase; MAT, methionine adenosyltransferase.

FIGURE 5

HGF-LKB1/AMPK signaling and AdoMet regulation. Although AMPK and LKB1 are traditionally thought of as metabolic tumor suppressors, they induce hepatocyte proliferation, via HuR cytoplasm translocation and stabilization of cyclin D1 and cyclin A expression, following hepatocyte growth factor (HGF) stimulation, and AdoMet can block this process. Activated AMPK induces the phosphorylation and activation of endothelial nitric oxide synthase (eNOS) leading to the generation of nitric oxide (NO). NO thus generated activates inducible NOS (iNOS) leading to a further increase in NO and the inactivation of MAT I/III. As a result, AdoMet content decreases releasing the inhibitory effect that this molecule exerts on LKB1 and AMPK phosphorylation via methylation and activation of phosphoprotein phosphatases 2A (Me-PP2A).

FIGURE 6

AdoMet catabolism. Excess AdoMet generated in the liver after a protein-rich meal is rapidly eliminated by the enzyme glycine N-methyltransferase (GNMT), which catalyzes the synthesis of methyl-glycine (sarcosine) from glycine. Sarcosine dehydrogenase (SDH) is a flavoprotein that catalyzes the oxidative demethylation of sarcosine to glycine. In this reaction, tetrahydrofolate (THF) is converted to 5,10-methyllenetrahydrofolate (5,10-MTHF).

FIGURE 7

Signaling pathways leading to HCC in AdoMet-deficient Mat1a KO mice. Several abnormal pathways have been identified in Mat1a KO mice that can contribute to hepatocellular carcinoma (HCC) formation: 1) a fall in apurinic/apyrimidinic endonuclease 1 (APEX1) activity, which leads to a reduction in DNA base excision repair, genome instability, and malignant transformation; 2) an increase in LKB1 activity, which induces the activation of AMPK and an increased translocation of HuR from the nucleus to the cytoplasm leading to the stabilization of several cyclin mRNAs and enhanced growth; 3) a reduction in prohibitin 1 (PHB1) content, which leads to impaired mitochondrial function and liver injury, increased cyclin D1 expression, and multifocal HCC; 4) a decrease in dual-specificity phosphatase 1 (DUSP1), which leads to uncontrolled ERK activation, a hallmark of HCC; and 5) expansion of tumorigenic oval stem cells positive for CD133, a cancer stem cell marker. See text for details.

FIGURE 8

Signaling pathways leading to HCC in Gnmt KO mice. Loss of GNMT activity induces an abnormal accumulation of hepatic AdoMet leading to a major epigenetic alteration in gene expression regulation. These epigenetic changes include the hypermethylation of Rassf1 and Socs2 promoters, as well as the trimethylation of histone 3 lysine 27 associated with these genes. As a consequence, the expression of Rassf1 and Socs2, as well as of other inhibitors of Ras and JAK/STAT signaling pathways, is downregulated. This leads to the activation of Ras and JAK/STAT signaling pathways, to abnormal growth, and to malignant transformation.