Galactosemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dayana Davidis, M.D. [2]
Overview
Pathophysiology
- Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development. [1]
Physiology
Galactose is metabolised in the body through the Leloir pathway. [2]
- It begins with conversion of B-D-galactose] to A-D-galactose catalysed by the enzyme galactose mutarotase
- A-D-galactose is then converted to galactose-1-phosphate by the enzyme galactokinase with utilisation of 1 molecule of ATP
- Galactose-1-phosphate combines with UDP-glucose to form UDP-galactose and the metabolically more useful glucose-1-phosphate with the help of the enzyme galactose-1-phosphate uridyl transferase.
- UDP-Galactose can undergo isomerisation in a reversible manner into UDP-glucose by the enzyme epimerase.
Pathology
Abnormalities in any of the enzymes involved in each of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.
- Deficiency or reduced activity of galactose-1-phosphate uridyl transferase enzyme leads to accumulation of galactose-1-phosphate [3] which:
- Sequesters phosphate essential for energy production in the human body [4]
- Inhibits enzymes involved in glucose metabolism, such as pyrophosphorylase [5]
- Inhibits galactosyl trasnferase thereby leading to defects in glycosylation [6]
- Galactokinase deficiency results in accumulation of galactose which gets converted to galactitol by a minor pathway.[7] This molecule predisposes to cataract by causing:
- Epimerase deficiency results in increased UDP-galactose and suppressed UDP-glucose with the ratio changing with the galactose concentration. This can have affects on the glycoprotein and glycolipid synthesis. [9]
- Galactose mutarotase enzyme deficiency results in galactose not being able to enter the Leloir pathway due to specificity of the enzymes for the B-isomer. This can have serious clinical consequences.[10]
References
- ↑ Coelho AI, Berry GT, Rubio-Gozalbo ME (2015). "Galactose metabolism and health". Curr Opin Clin Nutr Metab Care. 18 (4): 422–7. doi:10.1097/MCO.0000000000000189. PMID 26001656.
- ↑ Holden HM, Rayment I, Thoden JB (2003). "Structure and function of enzymes of the Leloir pathway for galactose metabolism". J Biol Chem. 278 (45): 43885–8. doi:10.1074/jbc.R300025200. PMID 12923184.
- ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1590/2326-4594-jiems-2021-002 Check
|pmid=value (help). - ↑ Gitzelmann R (1995). "Galactose-1-phosphate in the pathophysiology of galactosemia". Eur J Pediatr. 154 (7 Suppl 2): S45–9. doi:10.1007/BF02143803. PMID 7671964.
- ↑ Lai K, Langley SD, Khwaja FW, Schmitt EW, Elsas LJ (2003). "GALT deficiency causes UDP-hexose deficit in human galactosemic cells". Glycobiology. 13 (4): 285–94. doi:10.1093/glycob/cwg033. PMID 12626383.
- ↑ Coss KP, Treacy EP, Cotter EJ, Knerr I, Murray DW, Shin YS; et al. (2014). "Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism?". Mol Genet Metab. 113 (3): 177–87. doi:10.1016/j.ymgme.2014.08.004. PMID 25174965.
- ↑ Fekete E, Karaffa L, Sándor E, Bányai I, Seiboth B, Gyémánt G; et al. (2004). "The alternative D-galactose degrading pathway of Aspergillus nidulans proceeds via L-sorbose". Arch Microbiol. 181 (1): 35–44. doi:10.1007/s00203-003-0622-8. PMID 14624333.
- ↑ "StatPearls". 2022. PMID 32809518 Check
|pmid=value (help). - ↑ Openo KK, Schulz JM, Vargas CA, Orton CS, Epstein MP, Schnur RE; et al. (2006). "Epimerase-deficiency galactosemia is not a binary condition". Am J Hum Genet. 78 (1): 89–102. doi:10.1086/498985. PMC 1380226. PMID 16385452.
- ↑ Yazici H, Canda E, Altınok YA, Ucar SK, Coker M (2022). "Two siblings with galactose mutarotase deficiency: Clinical differences". JIMD Rep. 63 (1): 25–28. doi:10.1002/jmd2.12263. PMC 8743342 Check
|pmc=value (help). PMID 35028268 Check|pmid=value (help).