ACID STABILIZATION OF INSULIN

被引：58

作者：

BRYANT, C ^{[1
]}

SPENCER, DB ^{[1
]}

MILLER, A ^{[1
]}

BAKAYSA, DL ^{[1
]}

MCCUNE, KS ^{[1
]}

MAPLE, SR ^{[1
]}

PEKAR, AH ^{[1
]}

BREMS, DN ^{[1
]}

机构：

[1] ELI LILLY & CO,LILLY RES LABS,LILLY CORP CTR,INDIANAPOLIS,IN 46285

来源：

BIOCHEMISTRY | 1993年 / 32卷 / 32期

关键词：

D O I：

10.1021/bi00083a004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The effect of pH on the conformational stability of insulin was studied. Surprisingly, the Gibbs free energy of unfolding increased approximately 30% by acidification. pH titration of insulin's conformational stability is described by a transition involving a single proton with an apparent pK(a) of 7.0. The acid stabilization of insulin's conformation was attributed to the protonation of histidine at position 5 on the B-chain (H(B5)) as determined by H-1-NMR of the histidines, selective amino acid alteration, and enthalpies of ionization. Further acidification (at least to pH 2) does not decrease the free energy of unfolding. A conformational change in the tertiary structure, as indicated by the near-UV circular dichroism spectrum, accompanies this change in stability. We propose that this acid stabilization of insulin is physiologically important in maintaining insulin stability in the acid environment of the secretory/storage granules of the beta-cell of the pancreatic islets of Langerhans.

引用

页码：8075 / 8082

页数：8

共 33 条

[1] STRUCTURE OF RHOMBOHEDRAL 2 ZINC INSULIN CRYSTALS [J].

ADAMS, MJ ;

BLUNDELL, TL ;

DODSON, EJ ;

DODSON, GG ;

VIJAYAN, M ;

BAKER, EN ;

HARDING, MM ;

HODGKIN, DC ;

RIMMER, B ;

SHEAT, S .

NATURE, 1969, 224 (5218) :491-&

[2] STRUCTURE OF THE PIG INSULIN DIMER IN THE CUBIC-CRYSTAL [J].

BADGER, J ;

HARRIS, MR ;

REYNOLDS, CD ;

EVANS, AC ;

DODSON, EJ ;

DODSON, GG ;

NORTH, ACT .

ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1991, 47 :127-136

[3] THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5-A RESOLUTION [J].

BAKER, EN ;

BLUNDELL, TL ;

CUTFIELD, JF ;

CUTFIELD, SM ;

DODSON, EJ ;

DODSON, GG ;

HODGKIN, DMC ;

HUBBARD, RE ;

ISAACS, NW ;

REYNOLDS, CD ;

SAKABE, K ;

SAKABE, N ;

VIJAYAN, NM .

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES, 1988, 319 (1195) :369-&

[4] STRUCTURE OF INSULIN IN 4-ZINC INSULIN [J].

BENTLEY, G ;

DODSON, E ;

DODSON, G ;

HODGKIN, D ;

MERCOLA, D .

NATURE, 1976, 261 (5556) :166-168

[5] H-1 NUCLEAR MAGNETIC-RESONANCE STUDY OF THE HISTIDINE-RESIDUES OF INSULIN [J].

BRADBURY, JH ;

RAMESH, V ;

DODSON, G .

JOURNAL OF MOLECULAR BIOLOGY, 1981, 150 (04) :609-613

[6]

BRADER ML, 1991, TRENDS BIOCHEM SCI, V16, P341

[7] IMPROVED INSULIN STABILITY THROUGH AMINO-ACID SUBSTITUTION [J].

BREMS, DN ;

BROWN, PL ;

BRYANT, C ;

CHANCE, RE ;

GREEN, LK ;

LONG, HB ;

MILLER, AA ;

MILLICAN, R ;

SHIELDS, JE ;

FRANK, BH .

PROTEIN ENGINEERING, 1992, 5 (06) :519-525

[8] EQUILIBRIUM DENATURATION OF INSULIN AND PROINSULIN [J].

BREMS, DN ;

BROWN, PL ;

HECKENLAIBLE, LA ;

FRANK, BH .

BIOCHEMISTRY, 1990, 29 (39) :9289-9293

[9] STRUCTURE OF PIG AND SHEEP INSULINS [J].

BROWN, H ;

SANGER, F ;

KITAI, R .

BIOCHEMICAL JOURNAL, 1955, 60 (1-4) :556-565

[10] DETECTION OF AN EQUILIBRIUM INTERMEDIATE IN THE FOLDING OF A MONOMERIC INSULIN ANALOG [J].

BRYANT, C ;

STROHL, M ;

GREEN, LK ;

LONG, HB ;

ALTER, LA ;

PEKAR, AH ;

CHANCE, RE ;

BREMS, DN .

BIOCHEMISTRY, 1992, 31 (25) :5692-5698

← 1 2 3 4 →