SAH, S-adenosyl-homocystein sah

 Tämän  aminohapon ominaisarvosta HAKU: 

SAH on jäljellä kun SAM  (Aktivoitu  metioniini, S-adenosylmetioniini) on luovuttanut  metyyliryhmänsä (Ch3-) substraatille.  

 Metioniinia  voi palautua   mutta SAH muto omaa muitakin teitä.

 Mitä ne ovat?  Mikä merkitys on tällä välituotteella SAH?

Etsin artikkeleita, joissa se mainitaan SAH

(1)

 Targeting Histone Methylation

Marco P. Licciardello, Stefan Kubicek, in Drug Discovery in Cancer Epigenetics, 2016

Ten Ways to Target Histone Methylation 219

9.3.1 Methyltransferases can be Inhibited by Preventing SAH Turnover 219

9.3.2 Targeting the Peptide-Binding Pocket of Methyltransferases 221

9.3.3 The SAM-Binding Pocket as Universal Target of all Methyltransferases 222

9.3.4 Allosteric and Indirect Inhibition of Methyltransferases 222

9.3.5 Irreversible Inhibitors of LSD1/2 Covalently Bind the Cofactor FAD 222

9.3.6 The Emergence of the First Substrate Competitive LSD1 Inhibitors 224

9.3.7 Metabolic Targeting of JmjC Demethylases 224

9.3.8 Potent Small-Molecule Inhibitors Binding the Active Sites of JmjC Demethylases 224

9.3.9 PRMTs and PADs 225

9.3.10 Methylation Modulators of the Future 225

 

(2) 

https://doi.org/10.1016/S0065-3527(03)61014-6

Prospects for Antiviral Therapy The Flaviviruses: Detection, Diagnosis, and Vaccine Development

P. Leyssen, ... J. Neyts, in Advances in Virus Research, 2003

 S-adenosylhomocysteine Hydrolase

The SAH hydrolase is a pivotal enzyme in the regeneration cycle of S-adenosylmethionine (SAM). The latter serves as a methyldonor in methylation reactions such as those required for CAP formation. Inhibition of the SAH hydrolase leads to accumulation of SAH, which serves as an inhibitor of the SAM-dependent methylation reactions, including those required for maturation of viral RNA. A variety of carbocyclic adenosine analogues are assumed to exert their antiviral action through inhibition of the SAH hydrolase. In fact, a close correlation has been detected between the antiviral effects of various carbocyclic and acyclic adenosine analogues and their inhibitory effects on cell free SAH hydrolase (Cools and De Clercq, 1989). These compounds proved to be weak inhibitors of flavivirus replication in plaque reduction assays (Neyts et al., 1996; Tseng et al., 1989) relative to the potent activity they exert against the replication of ss(−)RNA viruses such as Ebola (Bray et al., 2000; Huggins et al., 1999). As outlined previously, however, SAH hydrolase inhibitors may possibly reduce the infectivity of newly formed virus particles and have a profound effect on second and further replication cycles.

(3)

• 2021;21(7):83846. 

S-adenosyl-L-homocysteine Hydrolase: Its Inhibitory Activity Against Plasmodium falciparum and Development of Malaria Drugs

Girish Chandra   ET AL. affiliations

PMID: 33342411 DOI: 10.2174/1389557521666201218155321

Abstract

Parasite Plasmodium falciparum is continuously giving a challenge to human beings by changing itself against most of the antimalarial drugs and its consequences can be seen in the form of a huge number of deaths each year especially in the poor and developing country. Due to its drug resistance ability, new drugs are regularly needed to kill the organism. Many new drugs have been developed based on different mechanisms. One of the potential mechanisms is to hamper protein synthesis by blocking the gene expression. S-Adenosyl-L-homocysteine (SAH) hydrolase is a NAD+ dependent tetrameric enzyme, which is responsible for the reversible hydrolysis of AdoHcy to adenosine and L-homocysteine (Hcy),    has been recognized as a new target for antimalarial agents since the parasite has a specific SAH hydrolase. The inhibition of SAH hydrolase causes the intracellular accumulation of S-Adenosyl-L-homocysteine, elevating the ratio of SAH to S-adenosylmethionine (SAM) and inhibiting SAM-dependent methyltransferase that catalyzes methylation of the capped structure at the 5'-terminus of mRNA, and other methylation reaction which is essential for parasite proliferation. In other words, S-Adenosyl-Lhomocysteine hydrolase regulates methyltransferase reactions. In this way, SAH hydrolase inhibitors can be used for the treatment of different diseases like malaria, cancer, viral infection, etc. by ultimately stopping the synthesis of protein. Many antiviral drugs have been synthesized and marketed which are based on the inhibition of SAH hydrolase. This review summarises the development of SAH inhibitors developed over the last 20 years and their potentiality for the treatment of malaria. Keywords: S-Adenosyl-L-homocysteine hydrolase; antimalarial compound; drug design; enzyme inhibitor; modified nucleoside; neplanocin. 

 

 (4) Pandemian päiviltä  SAH , Hcy , rikkipitoisten esentiellein aminohappojen metabolian välituotevaihe . Covid-19 infektion keuhkotilanteen   vaikeusasteen  biologinen merkitsijä, johon voidaan jokin verran vaikuttaa. 

Volume 2 | Issue 1 | DOI: https://doi.org/10.33696/cardiology.2.010  Predicting COVID-19 Hospitalized Patients’ Outcome with Homocysteine , Giovanni Ponti^1,*,et al. 

Homocysteine (Hcy), COVID-19 vulnerability, Predictor parameters, MTHFR gene, Biomarkers, MTHFR677C>T mutations .Commentary

In October 2020, we published ‘Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19’ [1]. Since then, recent scientific evidence from other authors [2-6], together with our own continuing research to include a larger cohort of hospitalized COVID-19 patients [7], has supported our original hypothesis, confirming that homocysteine (Hcy) is a predictive marker of COVID-19 outcome.

The COVID-19 pandemic has provoked a global, rapid increase of cases due to the high infectivity of the etiological agent, COVID-19 virus. In February 2021, over 110 million confirmed COVID-19 cases with 1 million deaths were reported worldwide (www.who.int).

Since the beginning of the pandemic, the identification of reliable biomarkers for COVID-19 disease progression has been a great challenge. Among various biomarkers tested, Hcy has sparked particular interest due to its association with both the metabolism of the SARS-CoV-2 virus and cardiovascular complications, which have proven to be the main cause of death among COVID-19 patients [8-10].

It is known that the SARS-CoV-2 virus transfers methyl group for viral RNA capping, from the host cell S-adenosylmethionine (SAM) converted into S-adenosylhomocysteine (SAH). SAH hydrolase (SAHH) removes adenosine from SAH, and produces an intermediate product called Hcy,  “homocysteine,” which is recycled by remethylation and the trans-sulphuration pathway in the human body [5,6,11,12].

Recently, novel regulatory mechanisms directly involved with Hcy in the activation of angiotensin II type receptor have been described [13]. Ferroptosis, a newly identified form of regulated cell death, does not share morphological, biochemical, or genetic similarities with other forms of regulated cell death, such as apoptosis [14]. It is characterized by the accumulation of iron and lipid reactive oxygen species (ROS) and by smaller mitochondria with condensed membrane densities. Increasing evidence suggests that ferroptosis dysfunction is positively related to several human diseases, including tumorigenesis [15]. Ferroptosis was found to be linked to common symptoms of COVID-19 disease, namely neurological disturbances, including cognitive impairment, ageusia, and anosmia (taste and smell loss) [16].

Regarding the genetic background of Hcy metabolisms, the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which produces methyl donor for the conversion of Hcy to methionine [17].

Hcy has been reported as a potential predictive biomarker for COVID-19 infection severity in many studies [1-4]. In a series of 273 Chinese hospitalized patients with mild COVID-19 disease, over 40 parameters were measured at admission. Disease progression was registered for 72 patients (computed tomography [CT] lung scans) and age, Hcy plasma levels and monocyte-to-lymphocyte ratio (MLR) were the only significant predictors in hyperhomocysteinemic patients (>15.4 μmol/L), estimated to correspond with a three-fold increased risk of disease evolution at radiological images. Interestingly, Hcy is the only predictive marker identified which is readily modifiable. Further, recent data confirmed the value of Hcy (together with age, MLR, and time from disease onset to hospital admission) in predicting the risk of severe pneumonia (on chest CT scan). The authors did not report any other additional organ involvement [3].

Our retrospective cohort study, including 313 COVID-19 hospitalized patients (female 34.8%; mean age 62 years) between April-September 2020, also included a broad panel of clinical laboratory data collected at admission. Of the enrolled patients, 10.9% died during hospitalization (3% were transferred to other hospitals and were lost to follow-up). Hcy was found to be the strongest predictor of Covid-19 critical-progression leading to death. Univariate analysis demonstrated that age (OR 1.04), Hcy (OR 1.06), and Neutrophil/Lympocyte count ratio (OR 1.03) were significant predictors of critical progression leading to death and RBC (OR 0.68) and Lymphocytes count (OR 0.23) with benign outcome (Table 1). ROC analysis indicated Hcy cut off of 16 μmol/L for predicting COVID-19 infection outcome (sensitivity 40% and specificity 84%); patients with Hcy levels >16 μmol/L had significantly increased risk of in-hospital mortality (p=0.002) both as a continuous and dichotomic value. Our results demonstrate that Hcy is an effective predictive biomarker for hospitalized COVID-19 patients’ outcome.

 

Several studies have demonstrated the importance of vitamin supplementation in patients with the COVID-19 disease. Vitamin B supplements (especially B9 and B12) are able to normalize blood Hcy levels in both apparently healthy individuals and patients with a history of stroke or Parkinson’s disease [18-20]. It is reasonable to suggest that B vitamins and Folic acid integration may have protective clinical effects for patients with infectious disease, due to MTHFR 6₇₇T allele alteration or other pathologic conditions. The relationship between the prevalence of genetic polymorphisms of MTHFR C6₇₇T and COVID-19 incidence and mortality rates seems to be intriguing; it may be useful biomarker COVID-19 infection severity stratification and it may be used for preventive medical treatments and supplementations.

Hyper-homocysteinemia is related to many virus infection outcomes, including human hepatitis virus [21], human papilloma virus [22] and Human immunodeficiency virus [23,24]. B vitamins (B2, B3 and B6) have a key role in the enhancement of the immune system [25].

Even though Hcy has been proven as a critical biomarker of cardiovascular risk and complications in hospitalized COVID-19 patients, it has not yet been adopted in prospective studies for useful laboratory markers for the stratification of COVID-19 patients.

Hcy may be a valuable biomarker which can help clinicians identify patients who are at higher risk for severe COVID-19 infection. Hcy plasma levels are easily determined by a simple and affordable laboratory test.

The association between Hcy levels >16 μmol/L and worse COVID-19 prognosis should encourage preventive health programs aimed to supplement dietary group B vitamins and folic acid for COVID-19 patients.

https://www.hsph.harvard.edu/nutritionsource/folic-acid/

 Foolihapon toinen nimi on vitamiini 9 muualla maailmassa.