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Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE).
Mol Genet Metab. 2008 Feb; 93(2):160-71.MG

Abstract

Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprised of galactokinase (GALK), galactose 1-P uridylyltransferase (GALT), and UDP-galactose 4'-epimerase (GALE). Impairment of GALT or GALE in humans results in the potentially lethal disorder galactosemia, and loss of either enzyme in yeast results in galactose-dependent growth arrest of cultures despite the availability of an alternate carbon source. In contrast, loss of GALK in humans is not life-threatening, and in yeast has no impact on the growth of cultures challenged with galactose. Further, the growth of both GALT-null and GALE-null yeast challenged with galactose is rescued by loss of GALK, thereby implicating the GALK reaction product, gal-1P, for a role in the galactose-sensitivity of both strains. However, the nature of that relationship has remained unclear. Here we have developed and applied a doxycycline-repressible allele of galactokinase to define the quantitative relationship between galactokinase activity, gal-1P accumulation, and growth arrest of galactose-challenged GALT or GALE-deficient yeast. Our results demonstrate a clear threshold relationship between gal-1P accumulation and galactose-mediated growth arrest in both GALT-null and GALE-null yeast, however, the threshold for the two strains is distinct. Further, we tested the galactose-sensitivity of yeast double-null for GALT and GALE, and found that although loss of GALT barely changed accumulation of gal-1P, it significantly lowered the accumulation of UDP-gal, and also dramatically rescued growth of the GALE-null cells. Together, these data suggest that while gal-1P alone may account for the galactose-sensitivity of GALT-null cells, other factors, likely to include UDP-gal accumulation, must contribute to the galactose-sensitivity of GALE-null cells.

Authors+Show Affiliations

Department of Human Genetics, Emory University School of Medicine, Room 325.2 Whitehead Building, 615 Michael Street, Atlanta, GA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17981065

Citation

Mumma, Jane Odhiambo, et al. "Distinct Roles of galactose-1P in Galactose-mediated Growth Arrest of Yeast Deficient in galactose-1P Uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE)." Molecular Genetics and Metabolism, vol. 93, no. 2, 2008, pp. 160-71.
Mumma JO, Chhay JS, Ross KL, et al. Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE). Mol Genet Metab. 2008;93(2):160-71.
Mumma, J. O., Chhay, J. S., Ross, K. L., Eaton, J. S., Newell-Litwa, K. A., & Fridovich-Keil, J. L. (2008). Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE). Molecular Genetics and Metabolism, 93(2), 160-71.
Mumma JO, et al. Distinct Roles of galactose-1P in Galactose-mediated Growth Arrest of Yeast Deficient in galactose-1P Uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE). Mol Genet Metab. 2008;93(2):160-71. PubMed PMID: 17981065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE). AU - Mumma,Jane Odhiambo, AU - Chhay,Juliet S, AU - Ross,Kerry L, AU - Eaton,Jana S, AU - Newell-Litwa,Karen A, AU - Fridovich-Keil,Judith L, Y1 - 2007/11/05/ PY - 2007/08/17/received PY - 2007/09/24/revised PY - 2007/09/24/accepted PY - 2007/11/6/pubmed PY - 2008/4/4/medline PY - 2007/11/6/entrez SP - 160 EP - 71 JF - Molecular genetics and metabolism JO - Mol Genet Metab VL - 93 IS - 2 N2 - Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprised of galactokinase (GALK), galactose 1-P uridylyltransferase (GALT), and UDP-galactose 4'-epimerase (GALE). Impairment of GALT or GALE in humans results in the potentially lethal disorder galactosemia, and loss of either enzyme in yeast results in galactose-dependent growth arrest of cultures despite the availability of an alternate carbon source. In contrast, loss of GALK in humans is not life-threatening, and in yeast has no impact on the growth of cultures challenged with galactose. Further, the growth of both GALT-null and GALE-null yeast challenged with galactose is rescued by loss of GALK, thereby implicating the GALK reaction product, gal-1P, for a role in the galactose-sensitivity of both strains. However, the nature of that relationship has remained unclear. Here we have developed and applied a doxycycline-repressible allele of galactokinase to define the quantitative relationship between galactokinase activity, gal-1P accumulation, and growth arrest of galactose-challenged GALT or GALE-deficient yeast. Our results demonstrate a clear threshold relationship between gal-1P accumulation and galactose-mediated growth arrest in both GALT-null and GALE-null yeast, however, the threshold for the two strains is distinct. Further, we tested the galactose-sensitivity of yeast double-null for GALT and GALE, and found that although loss of GALT barely changed accumulation of gal-1P, it significantly lowered the accumulation of UDP-gal, and also dramatically rescued growth of the GALE-null cells. Together, these data suggest that while gal-1P alone may account for the galactose-sensitivity of GALT-null cells, other factors, likely to include UDP-gal accumulation, must contribute to the galactose-sensitivity of GALE-null cells. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/17981065/Distinct_roles_of_galactose_1P_in_galactose_mediated_growth_arrest_of_yeast_deficient_in_galactose_1P_uridylyltransferase__GALT__and_UDP_galactose_4'_epimerase__GALE__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(07)00415-5 DB - PRIME DP - Unbound Medicine ER -