PDBsum entry 1xd0

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Hydrolase PDB id
Protein chain
496 a.a. *
Waters ×142
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Acarbose rearrangement mechanism implied by the kinetic and analysis of human pancreatic alpha-amylase in complex with and their elongated counterparts
Structure: Alpha-amylase. Chain: a. Synonym: 1,4-alpha-d-glucan glucanohydrolase, pancreatic al amylase, pa. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: amy2a. Expressed in: pichia pastoris. Expression_system_taxid: 4922
2.00Å     R-factor:   0.175     R-free:   0.199
Authors: C.Li,A.Begum,S.Numao,K.H.Park,S.G.Withers,G.D.Brayer
Key ref:
C.Li et al. (2005). Acarbose rearrangement mechanism implied by the kinetic and structural analysis of human pancreatic alpha-amylase in complex with analogues and their elongated counterparts. Biochemistry, 44, 3347-3357. PubMed id: 15736945 DOI: 10.1021/bi048334e
03-Sep-04     Release date:   07-Dec-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04746  (AMYP_HUMAN) -  Pancreatic alpha-amylase
511 a.a.
496 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Alpha-amylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Endohydrolysis of 1,4-alpha-glucosidic linkages in oligosaccharides and polysaccharides.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   3 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     8 terms  


DOI no: 10.1021/bi048334e Biochemistry 44:3347-3357 (2005)
PubMed id: 15736945  
Acarbose rearrangement mechanism implied by the kinetic and structural analysis of human pancreatic alpha-amylase in complex with analogues and their elongated counterparts.
C.Li, A.Begum, S.Numao, K.H.Park, S.G.Withers, G.D.Brayer.
A mechanistic study of the poorly understood pathway by which the inhibitor acarbose is enzymatically rearranged by human pancreatic alpha-amylase has been conducted by structurally examining the binding modes of the related inhibitors isoacarbose and acarviosine-glucose, and by novel kinetic measurements of all three inhibitors under conditions that demonstrate this rearrangement process. Unlike acarbose, isoacarbose has a unique terminal alpha-(1-6) linkage to glucose and is found to be resistant to enzymatic rearrangement. This terminal glucose unit is found to bind in the +3 subsite and for the first time reveals the interactions that occur in this part of the active site cleft with certainty. These results also suggest that the +3 binding subsite may be sufficiently flexible to bind the alpha-(1-6) branch points in polysaccharide substrates, and therefore may play a role in allowing efficient cleavage in the direct vicinity of such junctures. Also found to be resistant to enzymatic rearrangement was acarviosine-glucose, which has one fewer glucose unit than acarbose. Collectively, structural studies of all three inhibitors and the specific cleavage pattern of HPA make it possible to outline the simplest sequence of enzymatic reactions likely involved upon acarbose binding. Prominent features incorporated into the starting structure of acarbose to facilitate the synthesis of the final tightly bound pseudo-pentasaccharide product are the restricted availability of hydrolyzable bonds and the placement of the transition state-like acarviosine group. Additional "in situ" experiments designed to elongate and thereby optimize isoacarbose and acarviosine-glucose inhibition using the activated substrate alphaG3F demonstrate the feasibility of this approach and that the principles outlined for acarbose rearrangement can be used to predict the final products that were obtained.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21111049 X.Qin, L.Ren, X.Yang, F.Bai, L.Wang, P.Geng, G.Bai, and Y.Shen (2011).
Structures of human pancreatic α-amylase in complex with acarviostatins: Implications for drug design against type II diabetes.
  J Struct Biol, 174, 196-202.
PDB codes: 3old 3ole 3olg 3oli
20159465 N.M.Koropatkin, and T.J.Smith (2010).
SusG: a unique cell-membrane-associated alpha-amylase from a prominent human gut symbiont targets complex starch molecules.
  Structure, 18, 200-215.
PDB codes: 3k8k 3k8l 3k8m
18214874 C.A.Tarling, K.Woods, R.Zhang, H.C.Brastianos, G.D.Brayer, R.J.Andersen, and S.G.Withers (2008).
The search for novel human pancreatic alpha-amylase inhibitors: high-throughput screening of terrestrial and marine natural product extracts.
  Chembiochem, 9, 433-438.  
18599462 N.Shah, D.A.Kuntz, and D.R.Rose (2008).
Golgi alpha-mannosidase II cleaves two sugars sequentially in the same catalytic site.
  Proc Natl Acad Sci U S A, 105, 9570-9575.
PDB codes: 3cv5 3czn 3czs
17592362 R.Quezada-Calvillo, C.C.Robayo-Torres, Z.Ao, B.R.Hamaker, A.Quaroni, G.D.Brayer, E.E.Sterchi, S.S.Baker, and B.L.Nichols (2007).
Luminal substrate "brake" on mucosal maltase-glucoamylase activity regulates total rate of starch digestion to glucose.
  J Pediatr Gastroenterol Nutr, 45, 32-43.  
16527688 C.C.Robayo-Torres, R.Quezada-Calvillo, and B.L.Nichols (2006).
Disaccharide digestion: clinical and molecular aspects.
  Clin Gastroenterol Hepatol, 4, 276-287.  
16817895 E.J.Rossi, L.Sim, D.A.Kuntz, D.Hahn, B.D.Johnston, A.Ghavami, M.G.Szczepina, N.S.Kumar, E.E.Sterchi, B.L.Nichols, B.M.Pinto, and D.R.Rose (2006).
Inhibition of recombinant human maltase glucoamylase by salacinol and derivatives.
  FEBS J, 273, 2673-2683.  
16030022 X.Robert, R.Haser, H.Mori, B.Svensson, and N.Aghajari (2005).
Oligosaccharide binding to barley alpha-amylase 1.
  J Biol Chem, 280, 32968-32978.
PDB codes: 1rp8 1rp9 1rpk
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.