Copper and SAHH

I’m still digging Methylation topic.

This time a piece in Richard Deth’s book (“Molecular Origins of Human Attention”) about SAHH and copper got my attention and I went to read the references.

I want to share a few highlights:

1. SAHH is copper-binding enzyme and copper availability regulates abundance of the enzyme: “Copper deficiency led to decreased levels of SAHH in the liver cytosols from both moderately and severely copper-deficient mice. A ≈45% decrease in SAHH levels was detected in both moderately and severely deficient mice” (R1)

2. “the liver contains ≈12 times more SAHH than the kidney, which in turn contains ≈5 times more SAHH than the brain.” (R1).

3. SAHH activity is regulated by the ratio NAD/NADH and adenosine level. NADH inhibits activity and must be removed and replaced with NAD to restore activity. So whichever cycle controls NAD/NADH ratio will be responsible for Methylation potential too. (R2)

4. But divalent Copper seems to inhibit SAHH activity by releasing the NAD cofactor from the enzyme (R3):

The experimental results showed that Cu²⁺ inhibited SAHH activity in a noncompetitive manner. Binding of Cu²⁺ to SAHH resulted in the release of NAD⁺ cofactors, explaining the loss of the enzymatic activity of SAHH.

However, Cu²⁺ is not the active form of copper that is found inside the cell - it’s Cu¹⁺ that is imported into the cell and distributed using GSH and chaperone proteins to the target enzymes.

My summary

1. Seems like copper deficiency should be avoided to ensure sufficient level of SAHH enzyme.

2. NAD to NADH ratio is critical. That is, timely NADH removal should be ensured.

3. Adenosine and homocysteine clearance is essential for SAHH to operate in the SAH-reducing direction.