Journal of the Pancreas Open Access

Keywords

Betaine; Bodily Secretions; Glycine NMethyltransferase; Methylation; Pancreatitis; Phosphatidylethanolamine N-Methyltransferase; S-Adenosylmethionine

Abbreviations

GNMT: glycine N-methyltransferase; SAH: Sadenosylhomocysteine; SAM: S-adenosylmethionine

Dear Sir,

The comprehensive review by Braganza and Dormandy on micronutrient therapy for chronic pancreatitis included emphasis on the role of methyl group and thiol metabolism [1]. I am writing to expand on the comments expressed in the letter by Rajesh et al. [2] and the reply by Dr. Braganza [3] in the July issue of JOP. Journal of the Pancreas (Online). These have served to highlight the results reported by Girish et al. in which they suggest that a deficiency of methyl groups may be a factor in the development of pancreatitis [4]. In their letter, Rajesh et al. cite our paper showing that pancreatic secretion in rats is compromised in folate deficiency [2]. There is a close relationship between folate and methyl group metabolism. Folate is required for the de novo synthesis of methyl groups. The ratio of Sadenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) is regulated by the enzyme glycine Nmethyltransferase (GNMT) under the control of a specific form of folate [5]. GNMT is very abundant in the exocrine cells of the pancreas [6] and in a subsequent publication we showed that SAM plays an important role in the secretory process from pancreatic exocrine cells [7]. In that paper we provided evidence that SAM might be needed for carboxymethylation of G proteins that are needed in the process of exocytosis. It should also be noted that the process of exocytosis involves the fusion and regeneration of membranes that are generated in the Golgi and the rough endoplasmic reticulum [8]. Tissues that are actively involved in exocrine secretion may then have an increased requirement for synthesis of phosphatidylcholine, an important component of the plasma membrane. There are two pathways that are used for the synthesis of phosphatidylcholine. The major pathway in most tissues utilizes preformed choline reacting with cytidine triphosphate to eventually form phosphatidylcholine. The second pathway occurs primarily in the liver and message for it is present in other tissues including pancreas [9]. It involves the sequential methylation of phosphatidylethanolamine by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT) [10]. Thus three molecules of SAM are used for each molecule of phosphatidylcholine synthesized. The decreased plasma methionine and increased homocysteine plus the reduced level of folate in these patients suggest a diminished ability to remethylate homocysteine in chronic pancreatitis as suggested by Girish et al. [4]. It would be of interest to measure plasma levels of SAM and SAH in this group of patients in order to determine whether decreased methylation may be the underlying reason for the pancreatitis. In addition, dietary supplementation with methyl donors, such as betaine [11] that have been used to treat patients with cystathionine-beta-synthase deficiency, may be of use in treatment of chronic pancreatitis.

Conflict of interest

The author has no potential conflict of interest

References

1. Braganza JM, Dormandy TL. Micronutrient therapy for chronic pancreatitis: rationale and impact. JOP. J Pancreas (Online) 2010; 11:99-112. [PMID 20208316]
2. Rajesh G, Girish BN, Vaidyanathan K, Saumya M, Balakrishnan V. Folate deficiency in chronic pancreatitis. JOP. J Pancreas (Online) 2010; 11:409-10. [PMID 20601824]
3. Braganza JM. Reply to 'Folate deficiency in chronic pancreatitis'. JOP. J Pancreas (Online) 2010; 11:413-4.
4. Girish BN, Vaidyanathan K, Rao NA, Rajesh G, Reshmi S, Balakrishnan V. Chronic pancreatitis is associated with hyperhomocysteinemia and derangements in transsulfuration and transmethylation pathways. Pancreas 2010; 39:e11-6. [PMID 20050230]
5. Luka Z, Mudd SH, Wagner C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem 2009; 284:22507-11. [PMID 19483083]
6. Yeo EJ, Wagner C. Tissue distribution of glycine Nmethyltransferase, a major folate-binding protein of liver. Proc Natl Acad Sci USA 1994; 91:210-4. [PMID 8278367]
7. Capdevila A, Decha-Umphai W, Song KH, Borchardt RT, Wagner C. Pancreatic exocrine secretion is blocked by inhibitors of methylation. Arch Biochem Biophys 1997; 345:47-55. [PMID 9281310]
8. Fagone P, Jackowski S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res 2009; 50(Suppl):S311- 6. [PMID 18952570]
9. PEMT expression levels: phosphatidyl ethanolamine Nmethyl transferase. Gene Cards. Version 3. Rehovotm, Israel: Weizmann Institute of Science.
10. Vance DE, Walkey CJ, Cui Z. Phosphatidyl ethanolamine Nmethyl transferase from liver. Biochim Biophys Acta 1997;1348:142- 50. [PMID 9370326]
11. Dudman NP, Guo XW, Gordon RB, Dawson PA, Wilcken DE. Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. J Nutr.1996; 126(4 Suppl):1295S-300S. [PMID 8642474]