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Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

aging lifespan methionine restriction methylation methyltransferases s‐adenosylmethionine

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#1 Engadin

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Posted 04 September 2019 - 03:52 PM





F U L L   T E X T   S O U R C E :   Willey Online Library - Aging Cell






Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S‐adenosylmethionine, which, after transferring its methyl group, is converted to S‐adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.
Methionine is an essential proteogenic amino acid necessary for normal growth and development and is one of the four common sulfur‐containing amino acids (methionine, cysteine, homocysteine, and taurine). In humans, methionine can be obtained from food or from gastrointestinal microbes. Methionine plays a well‐known role as an initiator of protein synthesis in prokaryotes and eukaryotes and functions as an endogenous antioxidant at the surface of proteins (Levine, Mosoni, Berlett, & Stadtman, 1996; Luo & Levine, 2009). In addition, methionine serves major roles through its metabolism, which fuels a variety of metabolic pathways. Methionine metabolism can be broken into three parts: the methionine cycle, the transsulfuration pathway, and the salvage cycle (Figure 1).




FIGURE 1: Schematic of methionine metabolism



1.1 Methionine cycle

The first step in methionine metabolism is performed by methionine adenosyltransferase (MAT), an enzyme conserved from Escherichia coli to humans that catalyzes the biosynthesis of S‐adenosylmethionine (SAM) from methionine and ATP. SAM is the principal methyl donor and the second most widely used enzyme substrate after ATP (Cantoni, 1975). During substrate methylation, SAM donates its methyl group to acceptor molecules, for example, DNA, RNA, proteins, or other cellular metabolites, generating S‐denosylhomocysteinee (SAH). Over 200 known or putative methyltransferases have been identified in the human genome (Petrossian & Clarke, 2011) and 81 in yeast (Petrossian & Clarke, 2009). S‐denosylhomocysteine hydrolase (SAHH/AHCY) catalyzes the reversible hydrolysis of SAH to adenosine and l‐homocysteine. SAHH/AHCY proteins are tetramers with a NADH/NAD+ cofactor bound in the active site of each subunit (Brzezinski, Bujacz, & Jaskolski, 2008). There are also two AHCY‐like proteins, AHCYL1 and AHCYL2, which most likely have lost their canonical enzymatic functions due to critical mutations in their AHCY domains. However, via hetero‐multimerization, ACHYL1 and AHCYL2 can suppress the enzymatic activity of AHCY and thus act as dominant negative regulators of canonical AHCY (Devogelaere, Sammels, & Smedt, 2008). Cells must maintain low concentrations of SAH, which is a product inhibitor of SAM‐dependent methylation reactions. Methyltransferases catalyze a variety of methylation reactions via the transfer of methyl groups on histone proteins as well as to nucleic acids, nonhistone proteins, and metabolites, although different methyltransferases exhibit different sensitivity to inhibition by SAH (Huang et al., 2000). Homocysteine can be remethylated to form methionine and retained in the methylation cycle, or converted to cysteine via the transsulfuration pathway and thus withdrawn from the methylation cycle. Remethylation of homocysteine to form methionine completes the methionine cycle. This process involves either methionine synthase (MS), which requires 5‐methyltetrahydrofolate as a methyl donor, or betaine homocysteine methyltransferase (BHMT), which requires betaine as a methyl donor.
1.2 Transsulfuration pathway
Homocysteine from the methionine cycle can also be utilized in the transsulfuration pathway to produce cysteine. Cystathionine‐β‐synthase is the first and rate‐limiting enzyme of the transsulfuration pathway, the primary metabolic pathway for the synthesis of cysteine. Cystathionine‐β‐synthase synthesizes cystathionine from the condensation of homocysteine and serine. Cystathionine is hydrolyzed by cystathionine‐γ‐lyase to produce cysteine, which is further used in the synthesis of proteins, glutathione, and taurine. Cystathionine‐γ‐lyase and cystathionine‐β‐synthase also catalyze the production of hydrogen sulfide (H2S) from cysteine and homocysteine. H2S is a signaling molecule and cytoprotectant with a wide range of physiological functions. H2S protects cells from oxidative stress and can modulate neuronal transmission, smooth muscle relaxation, release of insulin, and the inflammatory response. Activation of the transsulfuration pathway promotes the production of H2S (Kabil, Vitvitsky, & Banerjee, 2014; Wallace & Wang, 2015).
1.3 Salvage pathway and polyamine biosynthesis
The methionine salvage pathway, or 5′‐methylthioadenosine (MTA) cycle, regenerates methionine from SAM and is responsible for the production of polyamines (Minois, Carmona‐Gutierrez, & Madeo, 2011; Pegg, 2016). In the methionine salvage pathway, SAM is decarboxylated by AdoMet decarboxylase into decarboxylated SAM (dcSAM), which serves as an aminopropyl group donor. In parallel, arginase converts arginine into ornithine, which is then decarboxylated by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is further converted to spermidine and spermine through the consecutive action of two distinct aminopropyl transferases, spermidine synthase and spermine synthase, which use dcSAM as an aminopropyl donor. dcSAM is converted to MTA after the donation of an aminopropyl group for polyamine synthesis, and MTA is converted via six enzymatic steps back to methionine (Minois et al., 2011; Pegg, 2016). In addition to participating in methylation and synthesis of polyamines, SAM can also be activated by members of the radical SAM superfamily of enzymes that convert SAM to a highly oxidizing 5′‐deoxyadenosyl radical intermediate involved in a variety of reactions (Landgraf, McCarthy, & Booker, 2016).
Beside its proteogenic and metabolic roles, methionine can also serve as an antioxidant. Methionine is one of the major targets of reactive oxygen species (ROS). Surface‐exposed methionine residues of native proteins can be oxidized by ROS to R‐ and S‐methionine sulfoxide, which can be reduced back to methionine by methionine sulfoxide reductases.
Consistent with the importance of methionine metabolism in cellular physiology, dysregulation of methionine metabolism has been reported in multiple diseases. Moreover, methionine restriction (MetR) has been tested as a treatment for disease in a number of clinical trials. Six genetic conditions in humans are known to lead to methionine and homocysteine elevation, that is, hypermethioninemias and hyperhomocysteinemias, as a result of deficiencies of enzymes involved in methionine metabolism (MAT, CBS, GNMT, AHCY) or affecting the mitochondrial transporter citrin and fumarylacetoacetate hydrolase (FAH; Mudd, 2011). Hyperhomocysteinemia is a characteristic of aging and upregulated levels of homocysteine contribute to the pathogenesis of multiple age‐associated diseases, including cardiovascular dysfunction, decline in renal and cognitive functions, bone fractures, and others (Ostrakhovitch & Tabibzadeh, 2019). However, under certain circumstances hyperhomocysteinemia can be observed without any pathological changes; this raises a question whether homocysteine contributes to pathogenesis or only serves as a biomarker. In addition, multiple cancer types are auxotrophic for methionine due to changes in methionine metabolism (Agrawal, Alpini, Stone, Frenkel, & Frankel, 2012; Cavuoto & Fenech, 2012), a feature further exploited in a variety of therapeutic approaches (clinicaltrials.gov). In addition, 11C‐methionine is the most popular amino acid tracer for PET imaging of brain tumors (Glaudemans et al., 2013). Finally, MetR in rodents not only extends lifespan but also protects from visceral fat mass accumulation and from the negative effects of a high‐fat diet (Ables, Perrone, Orentreich, & Orentreich, 2012; Malloy et al., 2006; Orentreich, Matias, DeFelice, & Zimmerman, 1993; Wanders et al., 2018). Based on these results, MetR has also been tested in clinical trials of obese adults with metabolic syndrome (Plaisance et al., 2011).
In the following sections, we discuss how the different branches of methionine metabolism—the methionine cycle, the transsulfuration pathway, and polyamine metabolism—regulate lifespan (Figure 2) and discuss a potential mechanism linking methionine flux and lifespan regulation. We also review mechanisms of lifespan extension by MetR (Figure 3 and Table 1) with a main focus on the relevance of methionine metabolism and methyltransferases (Table 2) to lifespan extension. It should be noted that the mechanisms underlying lifespan extension by MetR and reprogramming of methionine metabolism (e.g., via activation of methionine metabolism flux) may overlap but are not identical. For example, both MetR and increasing SAH clearance as a result of the activation of flux via methionine metabolism can extend lifespan by impacting SAM/SAH level. However, as we discuss in this review, the methyltransferases affected by these two interventions and responsible for their lifespan phenotypes may differ.
Figure 2: Methionine metabolism and methyltransferases
Figure 3: Mechanisms of lifespan extension by methionine metabolism and methyltransferases
F O R   T H E   R E S T   O F   T H E   S T U D Y ,   P L E A S E   V I S I T   T H E   S O U R C E .

Edited by Engadin, 04 September 2019 - 03:52 PM.

Also tagged with one or more of these keywords: aging, lifespan, methionine restriction, methylation, methyltransferases, s‐adenosylmethionine

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