Disease relevance of ALG1

• The ALG1 gene product has been shown to catalyze the transfer of a mannosyl residue from GDP-mannose to the lipid-linked acceptor GlcNAc2, yielding Man beta 1-4GlcNAc2-lipid, in lysates from Escherichia coli transformants [1].

High impact information on ALG1

• PM ATPase is synthesized as a approximately 106-kD polypeptide that is not detectably modified by asparagine-linked glycosylation or proteolysis during transit to the plasma membrane [2].
• Incubation of fibroblast extracts with [(14)C]GlcNAc(2)-PP-dolichol and GDP-mannose indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-PP-dolichol at the cytosolic side of the endoplasmic reticulum [3].
• Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik [3].
• Among the mutants identified by this screen were sec59 (which encodes dolichol kinase) and a mutant that affects the activity of the ALG1-encoded mannosyltransferase that forms dolichol-PP-(GlcNAc)2Man1 [4].
• This was supported by the finding that this CDG patient was compound heterozygous for three mutations in the ALG1 gene, leading to the amino acid substitutions S150R and D429E on one allele and S258L on the other [5].

Biological context of ALG1

• A plasmid suppressor of alg1, PSA1, encodes a 361 amino-acid protein with homology to NDP-hexose pyrophosphorylases, the enzymes that catalyze the formation of activated sugar nucleotides [6].
• Thermosensitive mutants of Saccharomyces cerevisiae, affected in the endoplasmic reticulum (ER) located glycosylation, i.e. in Dol-P-Man synthase (dpm1), in beta-1,4 mannosyl transferase (alg1) and in alpha-1,3 mannosyltransferase (alg2), were used to assess the role of GDP-Man availability for the synthesis of dolichol-linked saccharides [7].
• The DNA region including the ALG1 gene was sequenced and found to contain an open reading frame of 1347 bases [8].
• Disruption of the 74-amino acid reading frame, which ended 42 bases upstream of the potential start codon for the ALG1 protein, showed it was not essential for viability [8].
• The gene ALG1 has been cloned by complementation of the temperature-sensitive mutation alg1-1 with a total genomic DNA library [1].

Anatomical context of ALG1

• Both lipids were used as substrates by a recombinant, soluble beta-1,4-mannosyltransferase. beta-[3H]Mannosylated lipids from this reaction were then used as substrates for the subsequent mannosyltransferases from yeast or rat liver microsomes [9].
• Asparagine-linked glycosylation (ALG) is one of the most common protein modification reactions in eukaryotic cells, as many proteins that are translocated across or integrated into the rough endoplasmic reticulum (RER) carry N-linked oligosaccharides [10].

Associations of ALG1 with chemical compounds

• The yeast gene ALG1 encodes a mannosyltransferase which participates in the formation of the lipid-linked precursor oligosaccharide for N-glycosylation by catalyzing the formation of dolichol pyrophosphate (Dol-PP)-GlcNAc2Man from GDP-Man and Dol-PP-Glc-NAc2 [8].
• Recently in vivo galactose incorporation in Saccharomyces cerevisiae has been demonstrated through the expression of human beta-1,4-galactosyltransferase in an alg1 mutant, suggesting the presence of a UDP-galactose transporter in S. cerevisiae (Schwientek, T., Narimatsu, H., and Ernst, J. F. (1996) J. Biol. Chem. 271, 3398-3405) [11].
• The first step in the assembly of the dolichol-linked oligosaccharides required for asparagine-linked glycosylation in eukaryotes is catalyzed by a tunicamycin-sensitive, dolichol phosphate-dependent N-acetylglucosamine-1-phosphate transferase (GPT) [12].
• Also, the substrate recognition of the core beta-1,4-mannosyltransferase from yeast has been investigated using a range of chitobiose derivatives as potential substrates [13].

Physical interactions of ALG1

• The two Alg1-containing complexes differ from one another in that one complex contains Alg2 and the other contains Alg11 [14].

Other interactions of ALG1

• We have identified mutations in ALG1 (ERC14), a gene required for N-glycosylation, which are inviable in a cln1 cln2 background but are rescued by over-expression of CLNs [6].
• The gene ALG1 has been mapped on chromosome II at a distance of 2.1 map units from LYS2 [1].
• The Saccharomyces cerevisiae ALG7, ALG1 and ALG2 genes, whose products function early in the dolichol pathway of protein N-glycosylation, are essential for cell viability, and perturbation in their expression causes G1-specific cell cycle arrest [15].
• Disruption of the ALG1 open reading frame by insertion of the URA3 gene showed that the ALG1 gene was essential for viability [8].
• The Saccharomyces cerevisiae alg (asparagine-linked glycosylation) mutants fail to synthesize oligosaccharide-lipid properly, and the alg9 mutant, accumulates Man(6)GlcNAc(2)-PP-Dol [16].

Analytical, diagnostic and therapeutic context of ALG1

• Complementary DNA encoding lysozyme was subjected to site-directed mutagenesis to have the Asn-X-Thr(Ser) sequence that is the signal for asparagine-linked glycosylation at the positions 49 [17].

References