ALDH2 and nitroglycerin

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Experiment

• Collected 20 livers of naturally aborted fetuses - obtained purified ALDH2 *1/*1 and AlDH2 *1/*2 enzymes
• Used recombinant enzyme for ALDH2 *2/*2
• Km and Vmax values from Lineweaver-Burk plots of the 4 types of ALDH2 enzymes

Article

ALDH2 *2

• Nitroglycerin - treatment for angina & heart failure
• ALDH2 forms NO, metabolite needed for nitroglycerin efficacy
• Inactive ALDH2 *2 allele associated with lack of efficacy of sublingual nitroglycerin in Chinese subjects

Figure 1 The geographic distribution of ALDH2504Lys allele frequency. The grey scale refers to the interpolated allele frequency and correspondences are on the right, e.g. 0.12 means an allele frequency of 12% in the region. The open red triangles represent the locations of the population samples. The encircling black lines are the 0.12 and 0.24 frequency borders. A similar format is used in Figure 2 and Figure 3.

Representative Lineweaver-Burk plots for GTN as the variable substrate for the fetal ALDH2*1/1 (A) and ALDH2*1/2 (B) and the recombinant ALDH2*1/1 (C) and ALDH2*2/2 (D) enzymes.

• Point mutation - G-->A transition
• 1510 nt.
• Glu --> Lys substitution in protein at position 504
• Autosomal dominant
• Tetrameric enzyme
• 6% activity for ALDH2 *1/*2

Problem

• ALDH2 possesses esterase activity - catalyzes the hydrolysis of nitroglycerin
• Examine the role of Glu504Lys mutation in nitroglycerin metabolic activation

What is ALDH2?

• ALDH2*1 allele - wild type
• functional enzyme
• Caucasians

• ALDH2*2 allele - mutant
• nonfunctional enzyme/partial loss of function
• 50% Eastern Asians

Conclusions

• A small Km indicates high affinity, meaning the rate will approach Vmax more quickly
• Vmax - maximum rate achieved
• Vmax/Km= nitroglycerin catalytic efficiency

• Glu504Lys mutation directly associated with catalytic efficiency (Vmax/Km)
• nitroglycerin metabolism was ~10x higher ALDH2 *1/*1
• Concluded that Lys504 allele contributes in part to the failure of an effective response to nitroglycerin
• This genetic factor should be considered when administering nitroglycerin to patients, especially Asians, ~50% having inactive ALDH2 allele

• Gene found on Chromosome 12, locus q 24.2
• Codes for the enzyme mitochondrial aldehyde dehydrogenase
• 2nd enzyme of the major oxidative pathway of alcohol metabolism

References

Edenberg, Howard J. "Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants." The Genetics of Alcohol Metabolism 30.1 (n.d.): 5-13. 2007. Web. 28 Nov. 2012. <http://pubs.niaaa.nih.gov/publications/arh301/5-13.pdf>.

Kang, TS, SW Woo, HJ Park, Y. Lee, and J. Roh. "Comparison of Genetic Polymorphisms of CYP2E1, ADH2, and ALDH2 Genes Involved in Alcohol Metabolism in Koreans and Four Other Ethnic Groups." NCBI. N.p., Apr. 2009. Web. 28 Nov. 2012. <http://http://www.ncbi.nlm.nih.gov/pubmed/19250143>.

Li, Dawei, Hongyu Zhao, and Joel Gelernter. "Strong Protective Effect of the Aldehyde Dehydrogenase Gene ( ALDH2) 504lys (*2) Allele against Alcoholism and Alcohol-induced Medical Diseases in Asians." 131.5 (2012): 725-37. Academic Search Premier. Web. 20 Nov. 2012. <http://web.ebscohost.com.ezproxy.roosevelt.edu:2048/ehost/detail?sid=72dc53cd-85c4-499b-ab21-59135db8991b%40sessionmgr112&vid=1&hid=110&bdata=Jn NpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=74220308>.

Yifeng, Li, Dandan Zhang, Wel Jin, Chunhong Shao, Pengrong Yan, Congjian Xu, Haihui Sheng, Jinde Yu, Yuying Xie, Yingnan Zhao, Dara Lu, Daniel W. Nebert, Donald C. Harrison, Wei Huang, and Li Jin. "Mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) Glu504Lys Polymorphism Contributes to the Variation in Efficacy of Sublingual Nitroglycerin." 116.2 (2005): n. pag. The Journal of Clinical Investigation. Feb. 2006. Web. 02 Dec. 2012. <http://web.ebscohost.com.ezproxy.roosevelt. edu:2048/ehost/pdfviewer/ pdfviewer?sid=2a3031a9-7b6a-4319-98ca-704f1dd35abd%40se ssionmgr104&vid=4&hid=110>.

Keith Starwalt