Yeast, Plants, Worms, and Flies Use a Methyltransferase to Metabolize Age-Damaged (<i>R,S</i>)-AdoMet, but What Do Mammals Do?

Vinci, Chris R.; Clarke, Steven

doi:10.1089/rej.2009.0956

Cited by 7 publications

(5 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mht1 and Sam4 deletion in yeast resulted in accumulation of the biologically inactive ( R , S ) form, indicating that these two enzymes play an important role in controlling the in vivo accumulation of spontaneously generated ( R , S )-AdoMet (256). Interestingly, Mht1 and Sam4 activities have not been detected in mammalian cells (257), which indicates that mammals limit ( R , S )-AdoMet accumulation using other mechanisms.…”

Section: Structure and Biosynthesis Of Adometmentioning

confidence: 99%

S-adenosylmethionine in Liver Health, Injury, and Cancer

Mato²

2012

Physiological Reviews

451

593

View full text Add to dashboard Cite

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.

show abstract

Section: Structure and Biosynthesis Of Adometmentioning

confidence: 99%

S-adenosylmethionine in Liver Health, Injury, and Cancer

Mato²

2012

Physiological Reviews

451

593

View full text Add to dashboard Cite

show abstract

“…It is likely that AdoMet present in the environment from decaying organisms may be largely racemized, and the ability of yeast cells to use R,S-AdoMet may given them a significant advantage in obtaining carbon, sulfur, and nitrogen. The capability to use the R,S as well as the S,S form of AdoMet as a nutrient source may, in fact, provide an evolutionary advantage to the yeast, as well as to other lower organisms containing (R,S)-AdoMet specific homocysteine methyltransferases (36). Interestingly, we have not detected any such activity in mammalian cells; how these cells limit (R,S)-AdoMet accumulation is still unknown (36).…”

Section: Discussionmentioning

confidence: 76%

Homocysteine Methyltransferases Mht1 and Sam4 Prevent the Accumulation of Age-damaged (R,S)-AdoMet in the Yeast Saccharomyces cerevisiae

Vinci¹,

Clarke²

2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The biological methyl donor S-adenosyl-L-methionine (AdoMet) is spontaneously degraded by inversion of its sulfonium center to form the R,S diastereomer. Unlike its precursor, (S,S)-AdoMet, (R,S)-AdoMet has no known cellular function and may have some toxicity. Although the rate of (R,S)-AdoMet formation under physiological conditions is significant, it has not been detected at substantial levels in vivo in a wide range of organisms. These observations imply that there are mechanisms that either dispose of (R,S)-AdoMet or convert it back to (S,S)-AdoMet. Previously, we identified two homocysteine methyltransferases (Mht1 and Sam4) in yeast capable of recognizing and metabolizing (R,S)-AdoMet. We found similar activities in worms, plants, and flies. However, it was not established whether these activities could prevent R,S accumulation. In this work, we show that both the Mht1 and Sam4 enzymes are capable of preventing R,S accumulation in Saccharomyces cerevisiae grown to stationary phase; deletion of both genes results in significant (R,S)-AdoMet accumulation. To our knowledge, this is the first time that such an accumulation of (R,S)-AdoMet has been reported in any organism. We show that yeast cells can take up (R,S)-AdoMet from the medium using the same transporter (Sam3) used to import (S,S)-AdoMet. Our results suggest that yeast cells have evolved efficient mechanisms not only for dealing with the spontaneous intracellular generation of the (R,S)-AdoMet degradation product but for utilizing environmental sources as a nutrient.Aging can be seen as the accumulation of damaged biomolecules over time (1-3). As such, understanding the mechanisms by which organisms can slow such accumulation, as well as how these mechanisms may themselves eventually break down and fail, is crucial to an understanding of the aging process. Repair pathways for damaged DNA have been well established (4); damaged proteins can be removed by a combination of proteolytic and repair pathways (3,(5)(6)(7)(8). However, we only are beginning to understand how cells can prevent the accumulation of damaged small molecules.To date, there are only a few pathways known for metabolizing damaged or unwanted small molecules. trans-Aconitate, the spontaneous degradation product of the citric acid cycle intermediate cis-aconitate, can be detoxified by the action of a specific methyltransferase (9). L-2-Hydroxyglutarate is formed as an abnormal byproduct when L-malate dehydrogenase uses ␣-ketoglutarate rather than oxalacetate as a substrate. The accumulation of the toxic L-2-hydroxyglutarate product is prevented, however, by the action of an enzyme that converts it back to ␣-ketoglutarate.

show abstract

“…The co‐product of the HMT‐catalyzed reaction, S ‐adenosylhomocysteine (SAH) – itself a methyltransferase inhibitor – can then be degraded by SAH hydrolases [17] . An alternative enzyme is likely required in mammalian cells and in bacteria that do not contain HMTs (only 18 % of bacteria have been reported to contain HMTs) [18,19] …”

Section: Figurementioning

confidence: 99%

“…[16] One such mechanism known for yeast, worms, plants, and flies is mediated by homocysteine S-methyltransferases (HMTs), which preferentially accept the (R,S)-SAM diastereomer as a methyl donor to generate l-methionine from homocysteine, preventing the cellular accumulation of (R,S)-SAM. [17][18][19] The coproduct of the HMT-catalyzed reaction, S-adenosylhomocysteine (SAH) -itself a methyltransferase inhibitor -can then be degraded by SAH hydrolases. [17] An alternative enzyme is likely required in mammalian cells and in bacteria that do not contain HMTs (only 18 % of bacteria have been reported to contain HMTs).…”

mentioning

confidence: 99%

“…[17] An alternative enzyme is likely required in mammalian cells and in bacteria that do not contain HMTs (only 18 % of bacteria have been reported to contain HMTs). [18,19] Previous work showed that domain of unknown function 62 (DUF62) proteins have SAM hydrolase activity. [20][21][22] The existence of an enzyme that degrades SAM is counterintuitive as biosynthesis of SAM is metabolically costly, [23] and the cell is poised to make use of the reactivity of the sulfonium center in various ways.…”

mentioning

confidence: 99%

See 1 more Smart Citation

An Enzyme Containing the Conserved Domain of Unknown Function DUF62 Acts as a Stereoselective (R_s,S_c)‐S‐Adenosylmethionine Hydrolase

et al. 2020

View full text Add to dashboard Cite

Homochirality is a signature of biological systems. The essential and ubiquitous cofactor S‐adenosyl‐l‐methionine (SAM) is synthesized in cells from adenosine triphosphate and l‐methionine to yield exclusively the (S,S)‐SAM diastereomer. (S,S)‐SAM plays a crucial role as the primary methyl donor in transmethylation reactions important to the development and homeostasis of all organisms from bacteria to humans. However, (S,S)‐SAM slowly racemizes at the sulfonium center to yield the inactive (R,S)‐SAM, which can inhibit methyltransferases. Control of SAM homochirality has been shown to involve homocysteine S‐methyltransferases in plants, insects, worms, yeast, and in ∼18 % of bacteria. Herein, we show that a recombinant protein containing a domain of unknown function (DUF62) from the actinomycete bacterium Salinispora tropica functions as a stereoselective (R,S)‐SAM hydrolase (adenosine‐forming). DUF62 proteins are encoded in the genomes of 21 % of bacteria and 42 % of archaea and potentially represent a novel mechanism to remediate SAM damage.

show abstract

Yeast, Plants, Worms, and Flies Use a Methyltransferase to Metabolize Age-Damaged (R,S)-AdoMet, but What Do Mammals Do?

Cited by 7 publications

References 20 publications

S-adenosylmethionine in Liver Health, Injury, and Cancer

S-adenosylmethionine in Liver Health, Injury, and Cancer

Homocysteine Methyltransferases Mht1 and Sam4 Prevent the Accumulation of Age-damaged (R,S)-AdoMet in the Yeast Saccharomyces cerevisiae

An Enzyme Containing the Conserved Domain of Unknown Function DUF62 Acts as a Stereoselective (R_s,S_c)‐S‐Adenosylmethionine Hydrolase

Contact Info

Product

Resources

About

Yeast, Plants, Worms, and Flies Use a Methyltransferase to Metabolize Age-Damaged (R,S)-AdoMet, but What Do Mammals Do?

Cited by 7 publications

References 20 publications

S-adenosylmethionine in Liver Health, Injury, and Cancer

S-adenosylmethionine in Liver Health, Injury, and Cancer

Homocysteine Methyltransferases Mht1 and Sam4 Prevent the Accumulation of Age-damaged (R,S)-AdoMet in the Yeast Saccharomyces cerevisiae

An Enzyme Containing the Conserved Domain of Unknown Function DUF62 Acts as a Stereoselective (Rs,Sc)‐S‐Adenosylmethionine Hydrolase

Contact Info

Product

Resources

About

An Enzyme Containing the Conserved Domain of Unknown Function DUF62 Acts as a Stereoselective (R_s,S_c)‐S‐Adenosylmethionine Hydrolase