MPST (22q12.3) Merkaptopyruvaatti sulfurtransferaasi, MST, TST2, TUM1

 Siirtää rikkijonin (S)  syanidille (CN)  merkaptopalorypälehapolta.

Official Symbol MPST

Official Full Name mercaptopyruvate sulfurtransferase

Gene type protein coding

Also known as MST; TST2; TUM1

Summary  This protein encoded by this gene catalyzes the transfer of a sulfur ion from 3-mercaptopyruvate to cyanide or other thiol compounds. It may be involved in cysteine degradation and cyanide detoxification. There is confusion in literature between this protein (mercaptopyruvate sulfurtransferase, MPST), which appears to be cytoplasmic, and thiosulfate sulfurtransferase (rhodanese, TST, GeneID:7263), which is a mitochondrial protein.

 Deficiency in MPST activity has been implicated in a rare inheritable disorder known as mercaptolactate-cysteine disulfiduria (MCDU). Alternatively spliced transcript variants encoding same or different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in duodenum (RPKM 33.5), liver (RPKM 30.3) and 25 other tissues See more

Orthologsmouse all

 

1. Characterization and interaction studies of two isoforms of the dual localized 3-mercaptopyruvate sulfurtransferase TUM1 from humans. Fräsdorf B, et al. J Biol Chem, 2014 Dec 12. PMID 25336638, Free PMC Article
2. Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase. Yadav PK, et al. J Biol Chem, 2013 Jul 5. PMID 23698001, Free PMC Article Abstract
   Mercaptopyruvate sulfurtransferase (MST) is a source of endogenous H2S, a gaseous signaling molecule implicated in a wide range of physiological processes. The contribution of MST versus the other two H2S generators, cystathionine β-synthase (CBS)  and γ-cystathionase (CTH) , has been difficult to evaluate because many studies on MST have been conducted at high pH and have used varied reaction conditions. In this study, we have expressed, purified, and crystallized human MST in the presence of the substrate 3-mercaptopyruvate (3-MP). The kinetics of H2S production by MST from 3-MP was studied at pH 7.4 in the presence of various physiological persulfide acceptors:
   cysteine, dihydrolipoic acid, glutathione, homocysteine, and thioredoxin, and in the presence of cyanide.
   The crystal structure of MST reveals a mixture of the product complex containing pyruvate and an active site cysteine persulfide (Cys(248)-SSH) and a nonproductive intermediate in which 3-MP is covalently linked via a disulfide bond to an active site cysteine. The crystal structure analysis allows us to propose a detailed mechanism for MST in which an Asp-His-Ser catalytic triad is positioned to activate the nucleophilic cysteine residue and participate in general acid-base chemistry, whereas our kinetic analysis indicates that thioredoxin is likely to be the major physiological persulfide acceptor for MST.
3. Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme. Billaut-Laden I, et al. Toxicol Lett, 2006 Aug 20. PMID 16545926Mercaptopyruvate sulfurtransferase (MPST) plays a central role in both cysteine degradation and cyanide detoxification. Moreover, deficiency in MPST activity has been suggested to be responsible for a rare inheritable disorder known as mercaptolactate-cysteine disulfiduria (MCDU). To date, no mutation of the human MPST gene has been reported. We developed a screening strategy to search for mutations in the MPST gene of 50 unrelated French individuals. Two intronic polymorphisms (IVS1-110C>G and IVS2+39C>T) and a nonsense mutation (Tyr(85)Stop) were identified and their functional consequences were assessed in vivo by measurement of erythrocyte MPST activity and/or in vitro using heterologous expression or transient transfection assay. The nonsense mutation likely leads to the synthesis of a severely truncated protein without enzymatic activity, as supported by our in vitro data. This work constitutes the first report of the existence of a functional genetic polymorphism affecting MPST and should be of great help to investigate certain disorders such as MCDU.
4. Cloning and sequence analysis of the human liver rhodanese: comparison with the bovine and chicken enzymes. Pallini R, et al. Biochem Biophys Res Commun, 1991 Oct 31. PMID 1953758
5. The non-canonical Hippo/Mst pathway in lymphocyte development and functions. Du X, et al. Acta Biochim Biophys Sin (Shanghai), 2015 Jan. PMID 25487919

 

Cys/Met aineenvaihdunnan B6 vitamiinista riippuvat entsyymit

Cys/Met metabolizm PLP-dependent (B6 vitamin)  enzyme

This family includes enzymes involved in cysteine and methionine metabolizm. The following are members:

Cystathionine gamma-lyase,  CTH  (CSE)
Cystathionine gamma-synthase, 
Cystathionine beta-lyase, ( bakteereilla   d-aminohappoav: ssa   beta-lyaasi)
Cystathione beta synthase  CBS

Tuottuu  myös H2S

 OAH/OAS sulfhydrylase,
O-succinylhomoserine sulfhydrylase
(Sulfhydrylaaseja ei ole ihmisellä, vaikka ihmsen mikrobiomissa niitä saattaa löytyä) . 

All of these members participate is slightly different reactions.
All these enzymes use PLP (pyridoxal-5'-phosphate) as a cofactor.

( Entsyyminimiä on luomakunnasta, joten täytyy hakea ihmisen vastaava entsyymi, jos sitä löytyy)

 

Ps. 89:15,16

6.2.2018,11:11.Sana psalmista 86:15,16.

(A Maskil of Ethan the Ezrahite) Blessed are the people who know the festal shout, who walk , o Lord, in the light of thy countenance; who exult in thy name all the day, and extol thy righteousness.

Jos betasolu alkaa olla glutamaattivoittoinen( excitatorista signaalivälittäjää sisältävä) ...

Aivosita tiedetään, että GLU-neuronit ja GABA neuronit  ovat erilaistuneet  ja moemmat ovat  elektrisesti stimuloituvia soluja. Astrosyytti on se meatbolinen hermokudossolu(glia) joka varmistaa GLN glutamiinin  saantia molemmille neuronityypeille.  erikosituneisa  neuroneisa on  entryymisetti, joka  tekee  excitatorisessa glutamiinsita glutamiinihappoa ja konsentroi niitä jyväsiin, joita sitten voi vapautua aktiopotentiaalista. Synapsirakoon vapautunut glutamaatti olisi toksista, jos  sitä ei samantein palautetasi takaisin rakkuloihin  astrosyytin puolelle aineenavaihduntaan.(uudelleen rikastetavaksi glutamiiniksi). Astrosyytti ei reagoi aktiopotentiaaliin.  se ei eritä  exciktatorista glutamaattia, vaan  tutotaa glutamiinia jonka lähettää taää neuronille. 

GABA-erginen  neuroni kerää myös  valmtia GABA- molekyyliä  Siihen tarvitaan jatkoentsyymeitä glutamiinista GABA. muotoon. GABA- on gamma- amino-voihappo ja siinä on yksi hiili vähemmän kuin glutamaatissa, jteon se ei palaudu takaisin glutamaatiksi, se on dekarboksyloitunut( CO2 irronnut) . Se voi vieolä  jatkossa deaminoitua ja muuttau  maitohappoa vastaavaksi OH-voihapoksi neuronissa ja siitä sitetn  esim yölevon aikana sitä palautetaan takaisin  sitruunahappokierron selektiiviseen kothaan jossa käsitellään 4 hiilen orgaanisia  happoja( meripihkahappo) iitä sitten sitruunahappokierto  saa tehtyä glutamiinia, joka voi uudestaan lähtä  astrosyytistä  I jompaan kumpaan neuroniin.  Siis aina muodostuu helpommin uutta  glutamaattia (GLU) kuin  uutta GABA:a.  Jonkin verran on neuronisaskin mitokondrioita, mutta ne eivät ole varsinaisesti mitään aineenavaihdunnallisia soluja, vaan neuroneita passaa noin 10-20 astrosyyttiä kutakin neuronia. 

 Jos nyt soveltaa tätä  Glu- GABA ajatusta  betasoluun, joka on  haimasaarekkeen soluista ainoa elektrisesti ärtyvä. ( Sellaisia eivät ole alfa- tai deltasolut)  ja kun tiedetään että beta-solusta kirjoitetaan artikkeleita milloin GABA ja milloin  GLU näkökohdasta, tulee mieleen: Miten tämä solu pärjäilee näiden kahden  erilaisen neuronaalisen välittäjäaineen hyödynnyksessä ja miten  se on järejstänyt GABA-reseptorit ja NMDA ja AMPA  ja mGLU metaboliset kainaattireseptoirt, sillä se on kuetinkin  ( kehon tärkeimmän polttoaineen glukoosin) metabolisessä  sensoroivassa piirissä   endokriinsesti erittävä  solu  Se sensoroi glukoosin tason systeemisesä verenkierrossa.  ja sen mukaan lähettää työvälinettä glukoosin nopeaksi lapioimiseksi kaikkialla kehossa solujen sisään.  Beta solu ei siis ole varsinainen aineenavihduntasolu ja se vähä glukoosi minkä se  käyttää sensorissaan, on sen  välttämätöntä omaa energiaa.  Siis betasolu ei ole se solu joka  hävittää  itse  verensokerit kehosta"( ei kai kukaan niin luulekaan) , vaan se on vain mittarisolu, sensori, (kuten silmä on valon sensori) 8 tai kora äänen sensori)  ja  ebntasolu on polttoaineen sensori ja sen täytyy  itsekin tulla toimeen pienellä sokeriosuudella.  ja sitten syntetisosida sitä työvälinettä joka on proteiiniketju. siis insuliinia.  Insuliini on myösnkuin  eräänlainen  sähköinen  apukeino, jonka asettuminen kontaktiin, reeptoriin kohdesoluissa  saa solut toimimaan siten että soekrit hulvahtavat solun sisään. Ei ne sokerit mene soluun siitä insuliinireseptorikohdasta. vaan  Se on kontaktikohta. kuin töpseli seinässä, jsota saa virran  lamppuun jne.  Vaan  siihen sokerin huovahtamiseen solun sisään on muita kanavia  ja proteiinimolekyylejä.  Siis tässä sähkönjohtotyössä on tärkeitä GABA ja GLU molekyylit ja niiden reseptorit  betasolussa. Varsinkin GLU-reseptoreita on  tässä erityisesti katsottu viime aikoina, esim  mKAR- kaianattireseptoreita.  Tässä pidän taukoa. Siis  betasolu asetata intrasellulaarisesti glutamaatijärjestelmää niihin insuliinirakkuloihin, jotka  sitten erittyvät solusta. Rakkulapinnassa a  on omat reseptorit ja  ne eivät  vaikutu aktiopotentiaalitavalla.  Pohdin tätä edelleen. 

Joka tapauksessa glutamaatin liiallinen painotus betasolussa on  jokin häiriötila. Sitä tarvitaan  rajallisesti, mutta liika on  toksista. mKAR  asia on tutkimuksissa.

Nat Med. 2015 Apr;21(4):363-72. doi: 10.1038/nm.3822. Epub 2015 Mar 16.

Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment.

Marquard J¹, Otter S², Welters A³, Stirban A⁴, Fischer A⁴, Eglinger J², Herebian D⁵, Kletke O⁶, Klemen MS⁷, Stožer A⁸, Wnendt S⁹, Piemonti L¹⁰, Köhler M¹¹, Ferrer J¹², Thorens B¹³, Schliess F⁴, Rupnik MS¹⁴, Heise T⁴, Berggren PO¹¹, Klöcker N⁶, Meissner T⁵, Mayatepek E⁵, Eberhard D¹⁵, Kragl M¹⁶, Lammert E².

Author information

Abstract

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

Comment in

• Diabetes: Dextromethorphan stimulates insulin secretion from pancreatic β cells--a new role for an old drug? [Nat Rev Endocrinol. 2015]
• Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs? [Nat Med. 2015]

Somatostatiini eritys ja tauriini

 http://www.ncbi.nlm.nih.gov/pubmed/6137267



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994409/
Pancreatic β-cells release insulin via an electrogenic response triggered by an increase in plasma glucose concentrations. The critical plasma glucose concentration has been determined to be ~3 mM, at which time both insulin and GABA are released from pancreatic β-cells. Taurine, a β-sulfonic acid, may be transported into cells to balance osmotic pressure.
 The taurine transporter (TauT) has been described in pancreatic tissue, but the function of taurine in insulin release has not been established. Uptake of taurine by pancreatic β-cells may alter membrane potential and have an effect on ion currents. If taurine uptake does alter β-cell current, it might have an effect on exocytosis of cytoplasmic vesicle. We wished to test the effect of taurine on regulating release of insulin from the pancreatic β-cell.

Results

In both cell lines, 1 mM glucose had no effect on insulin levels and served as a control. Cells starved of glucose had a significant reduction (p<0 .001="" 1="" 3="" a="" all="" alone.="" also="" as="" but="" cells.="" cells="" compared="" control="" controls="" either="" expected="" glucose="" higher="" in="" insulin="" interestingly="" level="" lower="" mm="" no="" of="" or="" other="" p="" plus="" present.="" resulted="" showed="" significantly="" similar="" statistically="" taurine="" than="" that="" the="" this="" to="" treated="" treatment="" treatments.="" was="" when="" with="">

Conclusions

Taurine administration can alter the electrogenic response in β-cell lines, leading to a change in calcium homeostasis and a subsequent decrease in intracellular insulin levels. The consequence of these actions could represent a method of increasing plasma insulin levels leading to a decrease in plasma glucose levels.

Background

The endocrine pancreas is regulated by neurotransmitters, including the use of glutamate and GABA to regulate insulin and glucagon release as well as somatostatin to regulate both α- and β-cell activities. For insulin release, a rise in extracellular glucose to ~3 mM initiates co-release of insulin and GABA [1]. The elevated glucose likely stimulates the release of insulin and GABA from the synapse-like microvesicles (SLMV) through changes in ion currents in β-cells [2,3]. While the insulin is free to move to the circulatory system through the interstitial fluid, GABA binds to GABA_A receptors on αcells, causing the hyperpolarization of the α-cells, and inhibiting release of glucagon. Glutamate released from α-cells binds to GluR4 receptors on δ-cells, increasing the release of SST [4]. SST binds either to the SSTR2 receptor on the α-cell or the SSTR1 and/or SSTR5 receptor on the β-cell. SSTR2 activation maintains the GABA-initiated inhibition of glucagon from α-cells, while the SSTR1/5 receptors are responsible for inhibiting insulin release [5].

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid and is developmentally high in neonates, especially in the brain, and the levels decline to reach stable adult concentrations that are second to those of glutamate in the brain. In the adult, taurine is responsible for maintaining intracellular osmotic balance in a variety of cells examined [6-8]. In the non-obese diabetic mouse model, taurine alters islet development [9]. Previous work done in our laboratory demonstrate that taurine administration during early development in the mouse causes an increase in the number and size of pancreatic islets, without affecting the exocrine portion of the organ [10]. Further, resting plasma glucose levels in these mice were significantly lower than in age-matched controls (manuscript in preparation). When we examined the relative immunoreactivity of insulin, glucagon, and somatostatin in the pancreas of these mice, we found a significant increase in the levels of all three islet markers.

To determine the level at which taurine may interact with the pancreatic β-cells, we set out to test our hypothesis that taurine influences insulin release through its electrogenic transport into the cell. We used immunohistochemistry to address relative intracellular levels of insulin in Hit-T15 (pancreatic β-cell line) and Rin-m (insulinoma) cells.

Tauriinisupplementaatio ja haimasaakerefunktio leptiinivajeessa

https://www.ncbi.nlm.nih.gov/pubmed/25940922

Amino Acids. 2015 Aug;47(8):1533-48. doi: 10.1007/s00726-015-1988-z. Epub 2015 May 5.

Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls β, α, and δ-cell masses in genetic obese mice.

Santos-Silva JC¹, Ribeiro RA, Vettorazzi JF, Irles E, Rickli S, Borck PC, Porciuncula PM, Quesada I, Nadal A, Boschero AC, Carneiro EM.

Abstract

Taurine (Tau) regulates β-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release.
Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in β-cells and Ca(2+) oscillations were increased in α-cells.

 Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group.
In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and β-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating β-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.

PMID:

25940922

DOI:

10.1007/s00726-015-1988-z

[PubMed - indexed for MEDLINE]

Glukagonin eritys IDDM:ssä alfasoluista. Tauriinin osuus.

https://www.ncbi.nlm.nih.gov/pubmed/25393115

PLoS One. 2014 Nov 13;9(11):e113254. doi: 10.1371/journal.pone.0113254. eCollection 2014.

Possible contribution of taurine to distorted glucagon secretion in intra-islet insulin deficiency: a metabolome analysis using a novel α-cell model of insulin-deficient diabetes.

Bessho M¹, Murase-Mishiba Y¹, Imagawa A², Terasaki J¹, Hanafusa T¹.

Tiivistelmä, Abstract

Glykeminen epävakaus on vakava ongelma insuliinivajeisilla potilailla ja se saattaa osittain  johtua epänormaalista endogeenista glukagonin erityksestä. Ei ole tähän mennessä (2014) vielä   selvitetty insuliinivajeisessa tilassa esiintyvien  solunsisäisten aineenvaihdunnallisten mekanismien osuutta  poikkeavassa glukagonivasteessa. Tähän tutkimukseen tiedemiesryhmä kehitti erään solulinjan, jossa insuliinireseptorigeeni oli  poistettu,  siis  in vitro- alfa- solumalli  insuliinivajeisesta diabeteksesta (T1DM) ja siinä   glukoosivastte  oli epänormaalia.

• Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s) involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD), i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose.

 Tehtiin  kattava metabolomianalyysi näistä soluista. Löydettiin muutamia kandidaattimetaboliitteja, joiden pitoisuudet  erosivat huomattavasti vastaavien  kontrollisolujen pitoisuuksista   ja jotka saattaisivat  vaikuttaa glukagonin vapautumiseen insuliinireseoptorivajeisesta solusta. Näistä kandidaatimolekyyleistä tauriini oli huomattavasti  lisääntynyt insuliinireseptori-poistogeenisessä soluissa . Tauriini tunnistettiin  glukagonin stimuloijana  kontrollisoluissa.

 A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells) revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells.

 Tauriini myös  -   paradoksaalisesti - lisäsi liialliseksi   glukagonin eritystä korkeissa glukoosipitoisuuksissa niissä soluissa, joista puuttui insuliinireseptori. ja haimasaarekkeissa, joista.  insuliinireseptoria puuttui. Nämä tulokset viittaavat siihen, että  insuliinireseptorin ( insuliinivaikutuksen)  puuttuma alfasoluista ja  erityisesti tauriinin lisääntyminen, voi johtaa  kieroutuneeseen glukagonivasteeseen  näistä soluista . Tämä viittaisi tauriinin tärkeyteen  paradoksaalisesa glukagonivasteessa    ja siitä seuraavassa epävakaudessa, mikä insuliinivajeisessa diabeteksessa vallitsee.

 Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.

PMID:

25393115

PMCID:

PMC4231115

DOI:

10.1371/journal.pone.0113254

[Indexed for MEDLINE]

Free PMC Article

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