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Glycine Cleavage System

The Glycine Cleavage System is how the body processes glycine.

It is issues with this system which cause Nonketotic Hyperglycinemia.

The prologue: Folate One-Carbon Metabolism

Folate one-carbon metabolism (FOCM) is a network of interlinked reactions in which folates transfer one-carbon units required in different multi-step processes in the body.

Part of this large network is the Glycine Cleavage System.

Source: Prof. Nick Greene, UCL

The Glycine Cleavage System

In each of our cells have a little unit that acts as a power factory, called mitochondria. They create energy by respiration – taking in oxygen, oxidising organic substance, and releasing carbon dioxide. Inside the wall of this little power factory, loosely attached to the inner membrane there is a complex of four enzymes called the Glycine Cleavage System.

Enzymes are proteins used by the body to speed up reactions, which is handy – they also aren’t used up in the process, so can continue to do their thing over and over again. These particular four enzymes interact to break glycine down into other molecules when glycine levels get too high. It looks a bit like this:

This is an instance of the glycine cleavage system. It’s a complex of four enzymes:

  • the P protein  (encoded by the GLDC gene)
  • the H protein (encoded by the GCSH gene)
  • the L protein (encoded by the GCSL or DLD gene)
  • the T protein (encoded by the GCST or AMT gene)

These four little enzymes aren’t physically attached to each other, but instead they interact with each other in a sort of chemical dance. The Glycine Cleavage System uses these enzymes to perform a few chemical steps. The H-protein is the lead, and is responsible for interacting with the three other enzymes. It also acts as a shuttle, delivering some of the chemicals created in the process to other enzymes so they can do their parts.

This is a glycine enzyme. It is found all over the body, in blood, muscles, spinal fluid and in the brain. Glycine is the simplest amino acid and the body needs it for a lot of functions: fat metabolism, neurologic functions, muscle development and more. In NKH, it’s glycine the body isn’t able to process.

It has a chemical formula of NH2 – CH2 –COOH. The NH2 is the amine group and the COOH group is the carboxylic acid group. This is where they get their name amino acid. It’s also ambivalent, which means it can be found inside or outside a protein molecule.

Step 1 – The P Protein

When the glycine cleavage system comes across an extra glycine molecule, the H-protein taps the P protein to say its go time. The P-protein drops two hydrogen atoms, and then removes the carboxyl (the COO part) from the glycine, breaking them down into CO2.

The rest (a amine type group +H3N and a methyl group H2C) is given to the H-protein to deliver to the T-protein.

This is called Glycine decarboxylation.

Step 2 – The T Protein

The T-protein uses another molecule tetrahydrofolate (a derivative of folic acid) and works with the H-protein to create ammonia (NH4, from the amine group). It then joins the methyl group (CH2) with tetrahydrofolate to form a mash up, called 5,10methylenetrahydrofolate.

Step 3- The L Protein

Before the process, the H-protein had a carbon ring with two nice thiol groups (two sulfur atoms). Now the H-protein has a bit of a mess left, as both thiol groups have hydrogen atoms attached (HS). The H-protein needs to undergo an oxidation reaction to clean shop, and it taps the L-protein to help.

The L-protein takes the NAD+ molecules, and removes the H from sulfur atoms, allowing the H-protein to return to it’s original state.

Serine hydroxymethyltranferase (SHMT)

While that’s the end of the Glycine Cleavage Process, the glycine is only part way processed. Last we saw it, the glycine had been reduced down, and mashed in with the tetrahydrofolate (a derivative of folic acid) to become 5,10methylenetrahydrofolate.

Another process, called the Serine Hydroxymethyltranferase (SHMT) takes up the 5,10methylenetrahydrofolate and transfers the methyl group from 5,10methylenetrahydrofolate to another glycine molecule, which creates serine and our friend tetrahydrofolate (that folic acid derivative).


However, we know that NKH doesn’t have a problem in this area. If they did, they would have Smith-Magenis syndrome, rather than Non-ketotic Hyperglycinemia.