AHCY

Related Reading

S-adenosyl-L-homocysteine hydrolase dysfunction

Deleting the locus that overlaps the mouse AHCY gene caused embryonic death. Homozygous insertion mutations in the S-adenosine-L-homocysteine hydrolase gene in Arabidopsis thaliana resulted in zygotic lethality. In contrast, yeast mutants lacking Sah1 can survive due to another way to synthesize homocysteine. The homocysteine synthesized through this pathway can be further used for the synthesis of cysteine and glutathione as well as the synthesis of methionine and AdoMet. S-adenosine-L-homocysteine hydrolase deficiency in humans is a genetic disorder, the level of the plasma S-adenosyl-L-homocysteine (AdoHcy) is 150-fold higher than normal, and the ratio of AdoMet/AdoHcy is significantly reduced. In this disease, muscles, brain and liver are severely affected, it usually manifests as severe myopathy, slow myelination, developmental delay, and mild hepatitis. Biochemical analysis showed that the S-adenosine-L-homocysteine hydrolase activity in the liver, red blood cells and fibroblasts of patients with AHCY deficiency was only 3-20% of the mean control. At the cellular level, these patients showed a proliferation of smooth endoplasmic reticulum and reduction of rough endoplasmic reticulum, as well as hypermethylation of leukocyte DNA.

Figure 1. AdoMet-dependent methylation: the role of AdoHcy and S-adenosyl-L-homocysteine hydrolase a) in yeast and b) in mammals (Tehlivets, O.; et al. 2013)

S-adenosyl-L-homocysteine hydrolase: conservation and structure

S-adenosine-L-homocysteine hydrolase is a well-conserved enzyme, with more than 70% identity at the protein level between human and yeast orthologs, and is among the 90 most highly conserved yeast proteins, including actin (90%), histones (70–90%), ribosomal (70%), ubiquitin (90%), and heat shock proteins (70%). However, in some eukaryotic and many bacterial sequences, an insert of 40 amino acids is shown in the catalytic domain of this enzyme, and its function is still unknown. S-adenosine-L-homocysteine hydrolase belongs to the large family of NAD(P)H/NAD(P)⁺-binding proteins, and NAD(P)H/NAD(P)⁺ binding domains exist in many dehydrogenases and many other redox enzymes, but they are very unusual for hydrolases. Except for plants, all structurally characterized Sah1/AHCY proteins S-adenosine-L-homocysteine hydrolase are tetramers, which bind NADH /NAD⁺ cofactor in the active site of each subunit. In the L. luteus, S-adenosine-L-homocysteine hydrolase has been confirmed to function as a homodimer. The monomeric subunit of the protein consists of three domains: N-terminal substrate-binding domain, cofactor-binding domain and C-terminal tail.

Figure 2. S-adenosyl-L-homocysteine hydrolase: sequence and structural conservation (Tehlivets, O.; et al. 2013)

S-adenosyl-L-homocysteine hydrolase: regulation and localization

NAD⁺ is necessary to maintain the quaternary structure and catalytic activity of S-adenosine-L-homocysteine hydrolase, which makes the enzyme sensitive to the redox status of the cell that is reflected by the NAD⁺/NADH ratio. S-adenosyl-L-homocysteine hydrolase from the bovine kidney has two adenosine binding sites: a low-affinity binding site located in the catalytic domain and a high-affinity binding site located in the NAD⁺ / NADH binding domain site. The NAD⁺ form of S-adenosine-L-homocysteine hydrolase binds adenosine with low affinity, resulting in the formation of 3'-keto-adenosine and the reduction of the tight binding of NAD⁺ and NADH, and the protein adopts a closed conformation. However, the enzymatically inactive NADH form of the enzyme binds adenosine with high affinity, indicating the role of adenosine in NADH-induced inhibition of S-adenosine-L-homocysteine hydrolase and the potential function of the enzyme as intracellular Ado-binding protein. S-adenosine-L-homocysteine hydrolase has also been found to translocate into the nucleus in adult mammalian cells under hypoxia conditions known to induce transcriptional activity.

Conclusion

S-adenosine-L-homocysteine hydrolase has 70% identity between yeast and human orthologs, which can catalyze the reversible hydrolysis of AdoHcy into homocysteine and adenosine, and is one of the most conserved proteins S. cerevisiae, highlights its central role in cell metabolism. Homocysteine is related to many diseases, but the mechanism of these diseases is still elusive. Most importantly, since recently, AdoHcy rather than homocysteine has been recognized as a more sensitive marker for several homocysteine-related diseases. Yeast, as a validated unicellular model system, is particularly suitable for genomic methods, providing a new opportunity to explore the response of cells to AdoHcy accumulation. At present, some studies have confirmed that the system can be successfully used to identify and characterize AdoHcy responsive cellular processes related to humans.