Complex N<i>-</i>Acetylation of Triethylenetetramine

Cerrada-Gimenez, Marc; Weisell, Janne; Hyvönen, Mervi T.; Park, Myung Hee H; Alhonen, Leena; Vepsäläinen, Jouko; Keinänen, Tuomo A.

doi:10.1124/dmd.111.041798

Cited by 7 publications

(5 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, SSAT1 can also contribute to the metabolism of TETA when it is induced at relatively high level, which occurs under various conditions such as inflammation and oxidative stress (Pegg, 2008). The cell culture data are in agreement with our previous findings where SSAT1-deficient mice metabolized TETA at the same rate as wild-type mice did, but SSAT1 overexpressing mice displayed increased acetylation (Cerrada-Gimenez et al, 2011). The higher cellular accumulation of SpmTrien and its metabolism to TETA may offer means to improve achieving the effective therapeutic level in vivo by using SpmTrien as a bioactive precursor of TETA.…”

Section: Resultssupporting

confidence: 82%

“…SpmTrien (100-5000 mM) was incubated with 10-100 ng of human recombinant SSAT1 or SSAT2 for 10 minutes at +37°C and analyzed as described previously (Weisell et al, 2010;Cerrada-Gimenez et al, 2011). The end products were also analyzed by HPLC (Hyvönen et al, 1992) (detailed protocol in Supplemental data).…”

Section: Methodsmentioning

confidence: 99%

“…The polyamines Spd and spermine (Spm) are present at high concentrations in almost all cell types and are considered mediators of important cellular functions such as proliferation, differentiation, and tissue integrity (Pegg, 2009). We recently found that spermidine/spermine-N 1 -acetyltransferase (SSAT1), the key enzyme of polyamine catabolism, acetylates TETA in vitro and in vivo (Weisell et al, 2010;Cerrada-Gimenez et al, 2011). However, SSAT1-deficient (SSAT1-KO) mice metabolized TETA at the same rate as the wild-type mice, indicating the presence of other enzyme(s) mainly responsible for its metabolism.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase

et al. 2012

Self Cite

View full text Add to dashboard Cite

Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/ spermine-N 1 -acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.

show abstract

Section: Resultssupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…TETA forms two main metabolites in the body, monoacetyl-TETA and diacetyl-TETA [ 54 , 82 - 85 ]. Both acetyl metabolites are strong chelators in their own right, although their affinities for Cu (II) are substantially less than that of the parent compound [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation

Zhang

Liu

Amarsingh

et al. 2014

Cardiovasc Diabetol

View full text Add to dashboard Cite

BackgroundHeart disease is the leading cause of death in diabetic patients, and defective copper metabolism may play important roles in the pathogenesis of diabetic cardiomyopathy (DCM). The present study sought to determine how myocardial copper status and key copper-proteins might become impaired by diabetes, and how they respond to treatment with the Cu (II)-selective chelator triethylenetetramine (TETA) in DCM.MethodsExperiments were performed in Wistar rats with streptozotocin (STZ)-induced diabetes with or without TETA treatment. Cardiac function was analyzed in isolated-perfused working hearts, and myocardial total copper content measured by particle-induced x-ray emission spectroscopy (PIXE) coupled with Rutherford backscattering spectrometry (RBS). Quantitative expression (mRNA and protein) and/or activity of key proteins that mediate LV-tissue-copper binding and transport, were analyzed by combined RT-qPCR, western blotting, immunofluorescence microscopy, and enzyme activity assays. Statistical analysis was performed using Student’s t-tests or ANOVA and p-values of < 0.05 have been considered significant.ResultsLeft-ventricular (LV) copper levels and function were severely depressed in rats following 16-weeks’ diabetes, but both were unexpectedly normalized 8-weeks after treatment with TETA was instituted. Localized myocardial copper deficiency was accompanied by decreased expression and increased polymerization of the copper-responsive transition-metal-binding metallothionein proteins (MT1/MT2), consistent with impaired anti-oxidant defences and elevated susceptibility to pro-oxidant stress. Levels of the high-affinity copper transporter-1 (CTR1) were depressed in diabetes, consistent with impaired membrane copper uptake, and were not modified by TETA which, contrastingly, renormalized myocardial copper and increased levels and cell-membrane localization of the low-affinity copper transporter-2 (CTR2). Diabetes also lowered indexes of intracellular (IC) copper delivery via the copper chaperone for superoxide dismutase (CCS) to its target cuproenzyme, superoxide dismutase-1 (SOD1): this pathway was rectified by TETA treatment, which normalized SOD1 activity with consequent bolstering of anti-oxidant defenses. Furthermore, diabetes depressed levels of additional intracellular copper-transporting proteins, including antioxidant-protein-1 (ATOX1) and copper-transporting-ATPase-2 (ATP7B), whereas TETA elevated copper-transporting-ATPase-1 (ATP7A).ConclusionsMyocardial copper deficiency and defective cellular copper transport/trafficking are revealed as key molecular defects underlying LV impairment in diabetes, and TETA-mediated restoration of copper regulation provides a potential new class of therapeutic molecules for DCM.

show abstract

“…TETA can be administered for decades for the long-term treatment of Wilson disease with minor side effects [15,19]. Interestingly, TETA is rapidly metabolized by two acetyltransferases, thialysine Nε-acetyltransferase and spermidine/spermine N1-acetyltransferase-1 (SAT1) [20,21], the latter being the rate-controlling enzyme of polyamine catabolism.…”

Section: Introductionmentioning

confidence: 99%

Chemical activation of SAT1 corrects diet-induced metabolic syndrome

et al. 2020

Self Cite

View full text Add to dashboard Cite

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N 1 -acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

show abstract

Complex N-Acetylation of Triethylenetetramine

Cited by 7 publications

References 38 publications

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase

Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation

Chemical activation of SAT1 corrects diet-induced metabolic syndrome

Contact Info

Product

Resources

About

Complex N-Acetylation of Triethylenetetramine

Cited by 7 publications

References 38 publications

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N1-Acetyltransferase and Thialysine Acetyltransferase

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N1-Acetyltransferase and Thialysine Acetyltransferase

Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation

Chemical activation of SAT1 corrects diet-induced metabolic syndrome

Contact Info

Product

Resources

About

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N¹-Acetyltransferase and Thialysine Acetyltransferase