The metabolic origins of mannose in glycoproteins.
J Biol Chem
; 289(10): 6751-6761, 2014 Mar 07.
Article
em En
| MEDLINE
| ID: mdl-24407290
ABSTRACT
Mannose in N-glycans is derived from glucose through phosphomannose isomerase (MPI, Fru-6-P â Man-6-P) whose deficiency causes a congenital disorder of glycosylation (CDG)-Ib (MPI-CDG). Mannose supplements improve patients' symptoms because exogenous mannose can also directly contribute to N-glycan synthesis through Man-6-P. However, the quantitative contributions of these and other potential pathways to glycosylation are still unknown. We developed a sensitive GC-MS-based method using [1,2-(13)C]glucose and [4-(13)C]mannose to measure their contribution to N-glycans synthesized under physiological conditions (5 mm glucose and 50 µm mannose). Mannose directly provides â¼10-45% of the mannose found in N-glycans, showing up to a 100-fold preference for mannose over exogenous glucose based on their exogenous concentrations. Normal human fibroblasts normally derive 25-30% of their mannose directly from exogenous mannose, whereas MPI-deficient CDG fibroblasts with reduced glucose flux secure 80% of their mannose directly. Thus, both MPI activity and exogenous mannose concentration determine the metabolic flux into the N-glycosylation pathway. Using various stable isotopes, we found that gluconeogenesis, glycogen, and mannose salvaged from glycoprotein degradation do not contribute mannose to N-glycans in fibroblasts under physiological conditions. This quantitative assessment of mannose contribution and its metabolic fate provides information that can help bolster therapeutic strategies for treating glycosylation disorders with exogenous mannose.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas
/
Manose
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2014
Tipo de documento:
Article