Putative N-terminal splitting enzyme of amyloid A4 peptides is the multicatalytic proteinase, ingensin, which is widely distributed in mammalian cells.
The main characteristic changes observed in Alzheimer's disease (AD) are the presence of neurofibrillary tangles and the deposition of amyloid A4 peptides. The most abundant amyloid A4 peptide species in AD (which we tentatively named A4') is composed of 39 amino acids, which is devoid of the 3 N-terminal amino acids, Asp-Ala-Glu, of the originally reported A4 peptide. We synthesized a model peptide substrate, Suc-Ala-Glu-methylcoumarinamide (MCA), to identify the proteinase that splits the A4' peptide. DEAE-cellulose column chromatography of rat liver and porcine brain extracts showed that only one peak material digested the synthetic substrate at pH 8. The results for the final preparation indicate that the Suc-Ala-Glu-MCA-degrading enzyme is a high-molecular-mass proteinase, with a molecular mass of above 500,000, and is composed of several low-molecular-mass subunits. These results suggest that a non-lysosomal multicatalytic proteinase (we named this enzyme ingensin (ingens = large in Latin). Ishiura, S. et al. (1985) FEBS Lett. 189, 119-123) catalyzes the above reaction. Antiserum against the purified multicatalytic proteinase, ingensin, crossreacted with the purified Suc-Ala-Glu-MCA-degrading proteinase. It is likely that ingensin shows a similar action toward amyloid precursor protein (APP) in vivo.
Ishiura
S
S
National Institute of Neuroscience, NCNP, Tokyo, Japan.
Tsukahara
T
T
Tabira
T
T
Sugita
H
H
D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D015153:Blotting, Western; D002848:Chromatography, DEAE-Cellulose; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D009097:Multienzyme Complexes; D011498:Protein Precursors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex