Journal of Pediatric Gastroenterology & Nutrition:
Starch Digestion and Patients With Congenital Sucrase-Isomaltase Deficiency
Hamaker, Bruce R.*; Lee, Byung-Hoo*; Quezada-Calvillo, Roberto†
*Whistler Center for Carbohydrate Research, Department of Food Sciences, Purdue University, West Lafayette, Indiana
†Department of Chemistry, Universidad Autonoma de San Luis Potosi, San Luis Potosi, Mexico.
Address correspondence and reprint requests to Dr Bruce R. Hamaker, Whistler Center for Carbohydrate Research, Department of Food Sciences, Purdue University, West Lafayette, IN 47907-2009 (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Starch is the major carbohydrate storage type found in plant seeds and tubers in a semicrystalline form. Starch is consumed by humans as a major glucose source of dietary energy and it can supply as much as 70% to 80% of the calories in the overall average human diet (1–3). Starch has 2 main molecular structures: amylose, which consists of long linear chains of glucose associated by α-1,4 glucosidic linkages and occasional branching with α-1,6 linkages, and amylopectin consisting of relatively short α-1,4 bound glucose chains of variable length with a relatively high content of α-1,6 branching chains (Fig. 1, top left). Amylopectin, in particular, is an extremely large molecule containing approximately 1 million glucosyl units that lead to a complexity of branched structures that differs among genetic backgrounds (4–6). The proportion of amylose versus amylopectin, the average length of α-1,4-linked linear chains, and the frequency of α-1,6 branching vary considerably among starches. Such differences lead to variation in the digestion rate and production of α-amylase digestion products (7–9). These products, known as α-limit dextrins (Fig. 1, bottom), can modulate catalytic activities of the mucosal α-glucosidases.
COOKING RELATED TO HUMAN EVOLUTION
A new view on the human diet and evolution proposes that evidence of cooking up to 1.8 million years ago (10), and its accompanying gelatinization of starch in tubers and cereals, increased energy availability in prehistoric humans and was an evolutionary force for the development of modern humans. The importance of extracting maximum glucose from starchy foods for our ancestors cannot be overstated. What on cursory glance seems like a redundancy of enzymes to digest starch to glucose instead is an efficient, if not elegant, system for obtaining energy for the body.
PROCESS OF STARCH DIGESTION
In humans, the digestion of starch occurs by enzymatic hydrolysis during its transit through the gastrointestinal tract and requires the participation of 6 different α-glucosidic activities. Two luminal α-1,4 endoglucosidases, namely salivary and pancreatic α-amylases, hydrolyze linear unbranched starch segments with ≥5 glucose residues, releasing oligomers with from 2 (maltose, the simplest glucose oligomer) to 5 glucose residues, but with minimal production of free glucose (Fig. 1, top middle and right) (11). The segments containing α-1,6-linked branches are resistant to these α-amylase activities. To attain the effective release of free glucose, linear and branched glucose oligomers resulting from α-amylase digestion must be further hydrolyzed by 4 exohydrolases present in the mucosal epithelial cells of the small intestine (Fig. 1, bottom). These hydrolases comprise sucrase-isomaltase (SI) and maltase-glucoamylase (MGAM) complexes with C- and N-terminal enzymes, each composed of 2 α-glucosidases containing catalytic sites that act on the nonreducing ends of linear and branched glucose oligomers, with substantial release of free glucose monomers (12,13). All 4 enzymes have α-1,4 glucosidic activity and 1 enzyme, isomaltase, has substantial α-1,6 glucosidic activity that cleaves the linkages present in the branch points of α-limit dextrins. Individual MGAM and SI subunits share high sequence identity, approximately 40% to 60%. C-terminal enzymes have approximately 60% sequence identity, as do the N-terminal enzymes; however, sequence identity was relatively lower (approximately 40%) between C- and N-terminal α-glucosidases (Fig. 2) (14–16).
α-GLUCOSIDASES OF THE GASTROINTESTINAL TRACT
Salivary and pancreatic α-amylases are synthesized as approximately 78 kDa and are coded by the genes AMY1 and AMY2, respectively, located in the human chromosome 1. The typical human haploid genome contains 2 copies of AMY2 (AMY2 A and B) (17), but the presence of multiple copies of the segment containing both genes, AMY1 and 2, is common among normal human populations and seems to be associated with the amounts of starch ingested by particular human ethnic groups, suggesting that multiple copies of amylase genes is an adaptative feature for efficient digestion of high starch diets (18). The human α-amylases have specificity for the α-1,4 linked straight-chain regions of α-glucosyl polysaccharides. Human α-amylases have maximal specificity for the interior links, and the active sites bind 5 consecutive glucose residues at specific subsites, cleaving between the second and third subsites to form 2 smaller polymers (Fig. 1, top middle and right). Products that are smaller than the linear maltopentaose are unable to bind at all subsites, have low affinity for the active site of α-amylases, and the productive cleavage of these smaller oligosaccharides by α-amylases is markedly hampered. In addition, α-1,6 branching linkages interfere with the activity of α-amylases and may contribute to a slow digestion fraction observed in the hydrolysis products of starch. The sequential action of α-amylases promotes the release of linear glucose oligomers with 2 to 5 glucose residues together with larger and highly branched molecules, usually termed α-limit dextrins, as the main final products of luminal starch digestion.
Human MGAM contains 1857 amino acid residues, which after glycosylation and insertion in the apical membrane, displays a total molecular weight of close to 335 kDa (19,20). The cDNA sequences for the human enzyme have revealed the presence of 2 α-glucosidases in the mature protein (ct-MGAM and nt-MGAM), which display high sequence identity to the respective α-glucosidases of the SI complex and contain 1 potential active site (WIDMNE) in each. MGAM was originally described as 2 relatively thermoresistant maltase activities present in the human intestinal mucosa, and experimental evidence shows the existence of at least 2 subunits in the MGAM complex (21,22). Research has demonstrated that substantial differences in catalytic properties exist between the N- and C-terminal α-glucosidases of the enzyme (19,20). The C-terminal α-glucosidase shows a faster glucoamylase activity than the N-terminal α-glucosidase, but experiences substrate inhibition by the 3 to 5 series of glucose oligomers (maltotriose to maltopentaose) (Fig. 1, bottom middle). In contrast, the N-terminal α-glucosidase displays slower catalytic α-glucogenesis than the C-terminal α-glucosidase, but it shows much lower substrate inhibitory effect by the same glucose oligomers (11,23). In addition, clear differences of up to 2 orders of magnitude were observed in their degree of susceptibility to inhibition by acarbose, with the C-terminal α-glucosidase being more sensitive than the N-terminal α-glucosidase (24). The human MGAM gene (National Center for Biotechnology Information reference sequence NM_004668.2) is located in chromosome 7 (7q34). The human and mouse genomic projects have shown that the genomic region coding for MGAM of most mammalian species contains paralogous replications (4,5) of the 3′ segment coding for the C-terminal α-glucosidase of MGAM, each with potential for its transcription and alternative splicing. The recombinant mouse and human MGAM cDNA sequences show that the corresponding mRNAs are spliced alternatively in the segment corresponding to exons 22 to 44. In addition, the respective recombinant C-terminal proteins display variations in catalytic properties. These observations suggest that MGAM may be considered as a family of closely related proteins rather than a single unimodal protein and suggest that the catalytic properties of MGAM molecules may display variations depending on developmental stage, nutritional status, or diet. Its individual role in starch digestion, therefore, may require independent analysis and determination of the relative proportions of at least the most prominent splicing isoforms.
The gene coding for the human SI complex is located on chromosome 3q16, producing a protein with a predicted size of nearly 210 kDa (25,26). The mature SI is a complex composed of 2 α-glucosidases, sucrase and isomaltase (National Center for Biotechnology Information reference sequence NP_001032.2). After synthesis, the fully active proenzyme is transported and inserted in the apical membrane of the enterocytes through its N-terminus (27). Subsequently, SI is subjected to extracellular processing by pancreatic proteolytic enzymes in the intestinal lumen cleaving the complex and generating free sucrase and membrane-bound isomaltase subunits (28). The cleaved molecules remain associated to each other through noncovalent interactions. Both α-glucosidases display considerable α-glucosidic activity on starch-derived glucose oligomers. Human SI complex has an overall contribution of 60% to 80% of the total human intestinal maltase activity because of the amount of protein in the small intestine (29,30); however, the apparent Km values calculated for sucrase and isomaltase in association is at least 10 times higher than the apparent Km values calculated for the same activities of ct-MGAM (glucoamylase). The α-glucosidic activities of SI are, therefore, predominant in the human intestine but are a much slower glucose producer from glucose oligomers than is MGAM. The α-1,6 glucosidic linkage of the branched α-limit dextrins is hydrolyzed by the isomaltase of the SI complex. Although these branched linkages may contribute to the generation of “slow-digesting” products of starch digestion, SI displays approximately 50% as much debranching (isomaltase) activity as its maltase activity, which provides enough activity to cope with the total branched linkages that may be present during the starch digestive process (Fig. 1, bottom right).
Production of glucose from dietary starch depends on the orchestrated activities of SI and MGAM. Rates of substrate digestion depend on their specific interaction with 4 mucosal α-glucosidases. Control of glucogenesis can be obtained both through types of available substrates and inhibitory effects of oligomers on the different α-glucosidases.
GLYCEMIC RESPONSE DURING STARCH DIGESTION
Digestion of starch in the small intestine can occur rapidly, slowly, or not at all, and accordingly it has been nutritionally categorized in vitro as rapidly digestible starch (RDS), slowly digestible starch (SDS), and resistant starch (RS). In the in vitro Englyst et al (31) assay, RDS is digested within 20 minutes and correlated to the high glycemic index in that it leads to a sudden increase in the blood glucose level. In contrast, SDS is hydrolyzed at a much slower rate, and in the in vitro method is measured as glucose released from 20 to 120 minutes. RS, unlike RDS and SDS, cannot be digested in the small intestine and is used as dietary fiber in the large intestine (31,32). SDS has drawn interest because foods containing SDS are considered to have a glycemic index. Low glycemic index foods including SDS provide a moderated postprandial glucose response and extended glucose release and the possibility of reducing the risk of common chronic diet-related metabolic diseases (eg, type 2 diabetes mellitus, obesity, cardiovascular diseases) (33–38).
In patients with congenital sucrase-isomaltase deficiency (CSID), the only α-glucosidases present are the 2 MGAM subunits, commonly termed maltase and glucoamylase. Although these enzymes have the function of digesting α-amylase digestion products of starch to glucose, it is the full complement of MGAM and SI that efficiently accomplishes starch digestion. For starch digestion, that which is most missing in patients with CSID, is the debranching activity of isomaltase that is responsible for removing branches of the α-limit dextrins to linear maltooligosaccharides for rapid digestion by MGAM. Also missing is the abundance of the SI enzyme complex and its proposed role in slower digestion of starch-degradation products. The well-known sucrose malabsorption in CSID is often coupled with a problem of starch malabsorption. Undigested starch and sucrose molecules can also cause chronic diseases of the colon (eg, chronic osmotic diarrhea, abdominal pain) (39,40).
Possibilities of Increasing Starch Digestion by MGAM
One strategy for reducing starch malabsorption in patients with CSID would be to find ways to increase starch digestibility by MGAM so that undigested starch does not cause abdominal distress. A recent finding by our group shows that glucoamylase, also referred to as ct-MGAM, has high hydrolytic activity toward native starch molecules, so much so that it has been proposed to assist α-amylase in digesting starch (41). Starchy foods designed to be better digested by ct-MGAM would thus result in more complete digestion and glucose absorption in the small intestine. Such foods may include those with dispersed starch molecules that are found in well-gelatinized foods that include shear processes to break apart swollen starch granules (eg, purees, puddings, porridges). Maltodextrins, which are partially hydrolyzed starch-based products, would also likely be well digested by the MGAM enzymes, as would maltooligosaccharides (smaller breakdown products of starch).
Could Slowly Digestible Starchy Foods Be Better for Patients With CSID?
Another strategy for reducing abdominal distress experienced by some patients with CSID after consumption of starchy foods may be to consume slowly digestible, low-glycemic-response starchy foods. The reasoning here is that such starches digest slowly in the small intestine and can slow gastric emptying and motility of food (40), thus slowing starch delivery to the small intestine, where it would be better able to digest it, and that starch which enters the colon would do so in smaller amounts and during a longer postprandial period. As a result, bloating and osmotic effects of maltooligosaccharides in the bowel that can cause diarrhea would be reduced.
Slowly digestible starches can be found in a number of foods that have slowly digestible matrices (eg, al dente pasta, some whole-grain foods) and slowly digestible starch types (eg, moderately higher amylose cereals, partially gelatinized) (42). Consumption of these foods would represent a somewhat restrictive diet, which in the case of consumption of sucrose has been alleviated by supplementation with sacrosidase (43,44). Still, there is a fairly wide range of foods with slow digestible starch property. Other approaches that may be less restrictive in achieving slow starch digestion would include the addition of glucoamylase as a supplement or partial inhibition of α-amylase or MGAM, and disaccharides or maltooligosaccharides with α-linkages other than the 1,4 and 1,6 linkages found in starch molecules (eg, kojibiose, nigerose, isomaltulose).
1. French D. Whelan WJ. Chemistry and biochemistry of starch. Biochemistry of Carbohydrates
. London:Butterworth & Co; 1975. 267–335.
2. Lee PC. Digestibility of starches and modified food starches. J Pediatr Gastroenterol Nutr
3. Whistler RL, BeMiller JN. Carbohydrate Chemistry for Food Scientists. St. Paul, MN:American Association of Cereal Chemists; 1997.
4. Mua JP, Jackson DS. Fine structure of corn amylose and amylopectin fractions with molecular weights. J Agric Food Chem
5. Buleon A, Colonna P, Planchot V, et al. Starch granules: structure and biosynthesis. Int J Biol Macromol
6. Biliaderis CG. Walter RJ. Structure and phase transitions of starch polymers. Polysaccharide Association Structures in Food
. New York:Marcel Dekker; 1998. 57–168.
7. Ao Z, Simsek S, Zhang G, et al. Starch with a slow digestion property produced by altering its chain length, branch density, and crystalline structure. J Agric Food Chem
8. Zhang G, Ao Z, Hamaker BR. Nutritional property of endosperm starches from maize mutants: a parabolic relationship between slowly digestible starch and amylopectin fine structure. J Agric Food Chem
9. Zhang G, Sofyan M, Hamaker BR. Slowly digestible state of starch: mechanism of slow digestion property of gelatinized maize starch. J Agric Food Chem
10. Wrangham R. Catching Fire: How Cooking Made Us Human. New York:Basic Books; 2009.
11. Quezada-Calvillo R, Robayo-Torres CC, Ao Z, et al. Luminal substrate “brake” on mucosal maltase-glucoamylase activity regulates total rate of starch digestion to glucose. J Pediatr Gastroenterol Nutr
12. Jones BJ, Brown BE, Loran JS, et al. Glucose absorption from starch hydrolysates in the human jejunum. Gut
13. Gray GM. Starch digestion and absorption in nonruminants. J Nutr
14. Ernst HA, Lo Leggio L, Willemoës M, et al. Structure of the Sulfolobus solfataricus
α-glucosidase: implications for domain conservation and substrate recognition in GH31. J Mol Biol
15. Heymann H, Breitmeier D, Günther S. Human small intestinal sucrase-isomaltase: different binding patterns for malto- and isomaltooligosaccharides. Bio Chem Hoppe-Seyler
16. Robayo-Torres CC, Quezada-Calvillo R, Nichols BL. Disaccharide digestion: clinical and molecular aspects. Clin Gastroenterol Hepatol
17. Zabel BU, Naylor SL, Sakaguchi AY, et al. High-resolution chromosomal localization of human genes for amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1) by in situ hybridization. Proc Natl Acad Sci
18. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet
19. Nichols BL, Eldering J, Avery S, et al. Human small intestinal maltase-glucoamylase cDNA cloning. Homology to sucrase-isomaltase. J Biol Chem
20. Nichols BL, Avery S, Sen P, et al. The maltase-glucoamylase gene: common ancestry to sucrase-isomaltase with complementary starch digestion activities. Proc Natl Acad Sci U S A
21. Kelly JJ, Alpers DH. Properties of human intestinal glucoamylase. Biochim Biophys Acta
22. Dahlqvist A. The separation of intestinal invertase and three different intestinal maltases on TEAE-cellulose by gradient elution, frontal analysis and mutual displacement chromatography. Acta Chem Scand
23. Quezada-Calvillo R, Sim L, Ao Z, et al. Luminal starch substrate “brake” on maltase-glucoamylase activity is located within the glucoamylase subunit. J Nutr
24. Jones K, Sim L, Mohan S, et al. Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase. Bioorg Med Chem
25. Alpers DH, Helms D, Seetharam S, et al. In vitro translation of intestinal sucrase-isomaltase and glucoamylase. Biochem Biophys Res Commun
26. Chandrasena G, Osterholm DE, Sunitha I, et al. Cloning and sequencing of a full-length rat sucrase-isomaltase-encoding. Gene
27. Brunner J, Wacker H, Semenza G. Sucrase-isomaltase of the small-intestinal brush border membrane: assembly and biosynthesis. Methods Enzymol
28. Naim HY, Sterchi EE, Lentze MJ. Biosynthesis of the human sucrase-isomaltase complex. Differential O-glycosylation of the sucrase subunit correlates with its position within the enzyme complex. J Biol Chem
29. Semenza G, Auricchio S, Rubino A. Multiplicity of human intestinal disaccharidases I. Chromatographic separation of maltases and of two lactases. Biochim Biophys Acta
30. Semenza G, Auricchio S, Mantei N. Small intestinal disaccharidases. In: Scriver CR, et al., eds. Metabolic Basis of Inherited Disease.
New York: McGraw-Hill; 2001: 1623–50.
31. Englyst HN, Kingman SM, Hudson GJ, et al. Measurement of resistant starch in vitro and in vivo. Br J Nutr
32. Englyst HN, Kingman SM, Cummings JH. Classification and measurement of nutritionally important starch fractions. Eur J Clin Nutr
33. Ludwig DS. The glycemic index. JAMA
34. Jenkins DJA, Kendall CWC, Augustin LS, et al. Glycemic index: overview of implications in health and disease. Am J Clin Nutr
35. Jenkins DJA, Kendall CWC, McKeown-Eyssen G, et al. Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes. JAMA
36. Muir J, O’Dea K. Validation of an in vitro assay for predicting the amount of starch that escapes digestion in the small intestine of humans. Am J Clin Nutr
37. Opperman AM, Venter CS, Oosthuizen W, et al. Meta-analysis of the health effects of using the glycaemic index in meal-planning. Br J Nutr
38. Wolever TMS. Carbohydrate and the regulation of blood glucose and metabolism. Nutr Rev
39. Karnsakul W, Luginbuehl U, Hahn D, et al. Disaccharidase activities in dyspeptic children: biochemical and molecular investigations of maltase-glucoamylase activity. J Pediatr Gastroenterol Nutr
40. Treem WR. Congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr
41. Lin AH-M, Nichols BL, Quezada-Calvillo R, et al. Unexpected high digestion rate of cooked starch by the ct-maltase-glucoamylase small intestine mucosal α-glucosidase subunit. PLoS One
42. Zhang G, Hamaker BR. Slowly digestible starch: concept, mechanism, and proposed extended glycemic index. Crit Rev Food Sci
43. Treem WR, Ahsan N, Sullivan B, et al. Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency. Gastroenterology
44. Treem WR, McAdams L, Stanford L, et al. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr
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