Studies of S-adenosylhomocysteine-hydrolase polymorphism in a Croatian population

Kloor, Doris; Fumić, Ksenija; Attig, Sebastian; Tete, Martina; Oßwald, Hartmut; Barić, Ivo; Tomiuk, Jürgen; Kömpf, J.

doi:10.1007/s10038-005-0315-z

Cited by 5 publications

(7 citation statements)

References 12 publications

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“…7 Further, native-PAGE analysis shows an electrophoretic mobility for the analyzed recombinant proteins in accordance to the mobility of AdoHcyase isoforms from red blood samples as resolved by starch gel electrophoresis. 13 Thus, the p.R38W protein migrates slightly ahead of wildtype protein, whereas the p.G123R protein moves slowest (Figure 1b). The same behavior is observed for thrombindigested AdoHcyase proteins, indicating that the fusion part of the recombinant protein does not interfere with holoenzyme formation (Figure 1b).…”

Section: Resultsmentioning

confidence: 93%

“…Previously analyzed random blood samples from the hospital laboratory 13 exhibiting the electrophoretic behavior for SAHH 2, 3 and 4 were tracked down to the particular individuals. None of them had neither clinical symptoms reported so far in AdoHcyase deficiency, nor elevated plasma AdoHcy.…”

Section: Evaluation Of Adohcyase Isoform 2 3 Andmentioning

confidence: 99%

“…In the past, three polymorphic isoforms of AdoHcyase have been identified and only recently, a fourth variant has emerged. 13 In this report, we elucidate the role of identified polymorphisms at amino-acid position R38 and G123 for enzymatic activity and holoenzyme formation of AdoHcyase. We used circular dichroism to determine structural aspects such as protein unfolding and stability during thermal induction.…”

Section: Introductionmentioning

confidence: 98%

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Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

et al. 2006

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S-adenosylhomocysteine hydrolase (AdoHcyase) catalyzes the hydrolysis of AdoHcy to adenosine and homocysteine. Increased levels of AdoHcy may play a role in the development of cardiovascular diseases and numerous other conditions associated with hyperhomocysteinemia. Several polymorphic isoforms named SAHH-1 to 4 may be resolved by horizontal starch gel electrophoresis from red blood cells. We have identified the genetic background of isoforms SAHH-2 and SAHH-3. SAHH-2 represents the previously described polymorphism in exon 2 of the AdoHcyase gene (112 C4T; p.R38W). Isoform SAHH-3 is based on a new polymorphism in exon 3 (377 G4A), leading to the conversion of glycine to arginine at aminoacid position 123. To shed light on the effects of these polymorphisms on the molecular and catalytic properties of AdoHcyase, we made recombinant wild-type and polymorphic R38W and G123R enzymes for a comparative analysis. The amino-acid exchanges did not bring about major changes to the catalytic rates of the recombinant proteins. However, circular dichroism analysis showed that both polymorphisms effect the thermal stability of the recombinant protein in vitro, reducing the unfolding temperature by approximately 2.61C (R38W) and 1.51C (G123R) compared to wild-type protein. In view of the altered thermal stability, and slightly decreased enzymatic activity of polymorphic proteins (r6%), one may consider the analyzed AdoHcyase isoforms as risk markers for diseases caused by irregular AdoHcyase metabolism.

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Section: Resultsmentioning

confidence: 93%

Section: Evaluation Of Adohcyase Isoform 2 3 Andmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

et al. 2006

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“…These changes occurred despite only slight elevations in plasma homocysteine levels. 87,88 TREATMENT STRATEGIES Regardless of whether elevated SAH or hyperhomocysteinemia is more critical, both these conditions can be rectified by administration of betaine, 54,57 making betaine a very promising therapeutic agent. Furthermore, as a result of betaine preventing elevated SAH and hyperhomocysteinemia, it also prevents downstream consequences such as steatosis, apoptosis, accumulation of damaged proteins, and signaling defects.…”

Section: Defects In Crucial Methylation Reactionsmentioning

confidence: 99%

Alcoholic Liver Disease and Methionine Metabolism

Kharbanda¹

2009

Semin Liver Dis

102

121

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Alcoholic liver disease is a major health care problem worldwide. Findings have demonstrated that ethanol feeding impairs several of the multiple steps in methionine metabolism that leads to progressive liver injury. Ethanol consumption has been reported to predominantly inhibit the activity of a vital cellular enzyme, methionine synthase, involved in remethylating homocysteine. By way of compensation in some species, ethanol can also increase the activity of the enzyme, betaine homocysteine methyltransferase. This enzyme catalyzes an alternate pathway in methionine metabolism and utilizes hepatic betaine to remethylate homocysteine to form methionine and maintain levels of S-adenosylmethionine, the key methylating agent. Under extended periods of ethanol feeding, however, this alternate pathway cannot be maintained. This results in a decrease in the hepatocyte level of S-adenosylmethionine and increases in two toxic metabolites, S-adenosylhomocysteine and homocysteine. These changes in the various metabolites of methionine metabolism, in turn, result in serious functional consequences. These include decreases in essential methylation reactions by inhibiting various methyltransferases critical to normal functioning of the liver and upregulation of the activation of endoplasmic reticulum-dependent apoptosis and lipid synthetic pathways. The ultimate outcome of these consequences is increased fat deposition, increased apoptosis, accumulation of damaged proteins, and alterations in various signaling pathways, all of which can ultimately result in progressive liver damage. Of all the therapeutic modalities that are presently being used to attenuate ethanol-induced liver injury, betaine has been shown to be the most effective in a variety of experimental models of liver disease. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, reverses steatosis, prevents apoptosis and reduces both damaged protein accumulation and oxidative stress. Thus, betaine is a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.

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“…The inconsistent presence of hypermethioninaemia (or hypermethioninaemia below current cut-off values) makes newborn screening for this disease based on elevated methionine unreliable. The true incidence of this disorder is unknown, but studies based on the incidence of AdoHcy hydrolase polymorphisms in the Croatian population pointed to an approximate incidence of about 1:30 000 (Kloor et al 2006). Thus the disorder is probably largely underdiagnosed, not only owing to unawareness of its existence but also because of limited availability of specific tests (AdoMet, AdoHcy).…”

Section: Diagnosismentioning

confidence: 99%

Inherited disorders in the conversion of methionine to homocysteine

Barić

2009

J of Inher Metab Disea

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During the last decade much important new information relating to the metabolic pathway from methionine to homocysteine has been gained. Interest has been stimulated by the discovery of two novel disorders, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency. Another disorder in this pathway, methionine adenosyltransferase deficiency, has been increasingly detected, thanks to the expansion of newborn screening programmes by tandem mass spectrometry technology. These significant steps allow important insight into the pathogenesis of these three disorders, as well as into the mechanisms of damage to various organs (liver, brain, muscle) and point to the relevance of these disorders for crucial biological processes such as methylation, transsulfuration or carcinogenesis in mammals, the pathogenesis of numerous pathological conditions, in particular those associated with hyperhomocysteinaemia, the action and possible toxicity of some drugs or consequences of nutritional variations. This review summarizes current knowledge of three inherited disorders in this metabolic pathway and draws attention to their much broader significance for human health and understanding of important biological processes.

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Studies of S-adenosylhomocysteine-hydrolase polymorphism in a Croatian population

Cited by 5 publications

References 12 publications

Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

Functional analysis of human S-adenosylhomocysteine hydrolase isoforms SAHH-2 and SAHH-3

Alcoholic Liver Disease and Methionine Metabolism

Inherited disorders in the conversion of methionine to homocysteine

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