Homocamosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine

doi:10.1016/0009-8981(83)90243-7

Clinica Chimica Acta

Volume 132, Issue 2, 15 August 1983, Pages 157-165

https://doi.org/10.1016/0009-8981(83)90243-7 Get rights and content

Abstract

Patients afflicted with homocarnosinosis have elevated concentrations of homocarnosine in brain and CSF. It has been reported that they lack brain homocarnosinase. However, we have found that these patients are deficient in serum carnosinase, a dipeptidase which hydrolyzes homocarnosine about 5% as rapidly as it splits carnosine. Homocamosinase could not be detected in normal human brain extracts after isoelectric focusing or DEAE-cellulose column chromatography. The ability of brain extracts to hydrolyze homocarnosine thus appears to be attributable solely to the serum carnosinase which is present because of serum trapped in the brain sample. Preliminary data indicate that homocarnosinase is probably not present in 13 other human tissues. Normal CSF contained serum carnosinase, whereas the CSF of a homocarnosinosis patient was lacking this enzyme. Thus it appears that the elevated concentrations of homocarnosine in the CSF of homocarnosinosis patients are attributable to serum carnosinase deficiency.

References (16)

LR Gjessing et al.
Homocarnosinosis, a new metabolic disorder associated with spasticity and mental retardation
Lancet
(1974)
JF Lenney et al.
Homocarnosinase: a hog kidney dipeptidase with a broader specificity than carnosinase
Arch Biochem Biophys
(1977)
JF Lenney et al.
Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium
Clin Chim Acta
(1982)
WH Murphey et al.
Carnosinase: a fluorometric assay and demonstration of two electrophoretic forms in human tissue extracts
Clin Chim Acta
(1972)
TL Perry et al.
Serum carnosinase deficiency in carnosinemia
Lancet
(1968)
O Sjaastad et al.
Homocarnosinosis. 2. A familial metabolic disorder associated with spastic paraplegia, progressive mental deficiency, and retinal pigmentation
Acta Neurol Scand
(1976)
O Sjaastad et al.
Homocarnosinosis. 3. Spinal fluid amino acids in familial spastic paraplegia
Acta Neurol Scand
(1977)
SJ Kish et al.
Regional distribution of homocarnosine, homocarnosine-carnosine synthetase and homocarnosinase in human brain
J Neurochem
(1979)

There are more references available in the full text version of this article.

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^∗∗: Department of Neurology, Trondheim University Hospital, Trondheim, Norway. Enzymes: Carnosinase (EC 3.4.13.3); homocarnosinase (EC 3.4.13.13); aldolase (EC 4.1.2.13).

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Homocamosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine

Abstract

Lancet

Arch Biochem Biophys

Clin Chim Acta

Clin Chim Acta

Lancet

Homocarnosinosis. 2. A familial metabolic disorder associated with spastic paraplegia, progressive mental deficiency, and retinal pigmentation

Acta Neurol Scand

Homocarnosinosis. 3. Spinal fluid amino acids in familial spastic paraplegia

Acta Neurol Scand

Regional distribution of homocarnosine, homocarnosine-carnosine synthetase and homocarnosinase in human brain

J Neurochem