Serine hydroxymethyltransferase: Difference between revisions
No edit summary |
No edit summary |
||
| Line 13: | Line 13: | ||
=Mechanism of Action= | =Mechanism of Action= | ||
The most common accepted mechanism of action is through a process of modified retro-aldol cleavage. In this case, the mechanism starts with the serine/PLP-enzyme complex. The | The most common accepted mechanism of action is through a process of modified retro-aldol cleavage. In this case, the mechanism starts with the serine/PLP-enzyme complex. The base represented by 'B' attacks the hydrogen of the ethyl alcohol functional group. The resonance allows the process of tautomerization to occur. This end results of tautomerization results in the formation of a formaldehyde, and acidic 'H-A' compound, and an imine attached to the serine-PLP complex. The double bond of the imine then reacts with the acidic 'H-A' compound. Resonance then allows the new complex to form the separated glycine and PLP-enzyme. | ||
In the case of serine hydroxymethyltransferase, the pyridoxal-5'-phosphate is the cofactor. The SHMT enzyme has no enzymatic activity without the presence of this cofactor. For now, serine and tetrahydrofolate (THF) are the only known biological substrates of SHMT. The end products are of course glycine and 5,10-methylene tetrahydrofolate. As far as inhibitors, antifolates are known to reduce and/or eliminate the enzymatic activity of SHMT. This is not surprising because of the fact that folate compounds are substrates of SHMT. | |||
{{Clear}} | {{Clear}} | ||
[[Image:S_to_G_Mechanism.png|left|thumb|400px| Mechanistic Conversion of Serine to Glycine catalyzed by SHMT]] | [[Image:S_to_G_Mechanism.png|left|thumb|400px| Mechanistic Conversion of Serine to Glycine catalyzed by SHMT]] | ||
Revision as of 01:07, 3 December 2013
IntroductionIntroduction
|
FunctionFunction
Serine hydroxymethyltransferase (SHMT) is part of the pyridoxal phosphate (PLP)-dependent enzymes. The enzyme is broadly classified as a transferase enzyme. Transferase enzymes primarily work by catalyzing the transfer of a specific functional group from one molecule to another. For example, a methyl group may need to be transferred from one molecule to another in vivo. The transferase enzymes will catalyze the transfer of this methyl group.
Specifically, the enzyme belongs to the alpha-class. This enzyme is utilized mainly for two functions. First, the enzyme catalyzes the reversible conversion of L-serine to L-glycine. Second, the enzyme catalyzes the reversible conversion of tetrahydrofolate to 5,10-methylene tetrahydrofolate. The mechanism for the interconversion of both molecules is shown below.
Diversity/ImportanceDiversity/Importance
There appear to be multiple isoforms of the enzyme in bacteria. Serine hydroxymethyltransferase isoforms have namely been identified from Escherichia coli and Bacillus stearothermophilus. In mammals, there are two separate isoforms of SHMT in the cytoplasm and the mitochondria. In plants, there is an additional SHMT isoform found within the chloroplast. The diverse presence of serine hydroxymethyltransferase is in part because of the importance of 5,10-methylene tetrahydrofolate. This intermediate is important for the synthesis of the essential biomolecules purine, thymidine, choline, and methionine. Serine hydroxymethyltransferase plays a very important role in the Smith-Magneis syndrome (SMS). SHMT is also being studied in the field of anti-cancer and anti-microbials drugs.
FoldingFolding
The enzyme monomer fold is comprised of the c-terminal domain and the N-Terminal Domain. The C-terminal domain folds into an αβ sandwich. The N-terminal domain is comprised of two further domains. The first N-terminal sub-domain is a smaller domain composed of only 3 α-helices and 1 β-strand. The second N-terminal subdomain is the PLP binding domain. This sub-domain folds into an αβα structure that has a seven-stranded mixed β sheet surrounded by α-helices on both sides, hence αβα.
StructureStructure
Mechanism of ActionMechanism of Action
The most common accepted mechanism of action is through a process of modified retro-aldol cleavage. In this case, the mechanism starts with the serine/PLP-enzyme complex. The base represented by 'B' attacks the hydrogen of the ethyl alcohol functional group. The resonance allows the process of tautomerization to occur. This end results of tautomerization results in the formation of a formaldehyde, and acidic 'H-A' compound, and an imine attached to the serine-PLP complex. The double bond of the imine then reacts with the acidic 'H-A' compound. Resonance then allows the new complex to form the separated glycine and PLP-enzyme. In the case of serine hydroxymethyltransferase, the pyridoxal-5'-phosphate is the cofactor. The SHMT enzyme has no enzymatic activity without the presence of this cofactor. For now, serine and tetrahydrofolate (THF) are the only known biological substrates of SHMT. The end products are of course glycine and 5,10-methylene tetrahydrofolate. As far as inhibitors, antifolates are known to reduce and/or eliminate the enzymatic activity of SHMT. This is not surprising because of the fact that folate compounds are substrates of SHMT.
ImplicationsImplications
This enzyme has important implications in disease and medicine. Smith-Magneis syndrome (SMS) is a genetic disorder in which there is a defect in the short arm of chromosome 17. This disease causes mental retardation, behavioral problems, and gives the affected person an obvious set of facial features. The defect results in approximately a 50% loss of cytosolic-SHMT present in individuals. If there is less SHMT than needed, the products any SHMT catalyzed-reaction would be deficient.
One potential application for SHMT is in cancer-therapeutics. The enzyme is an important factor in rapidly dividing cells. This knowledge could turn into the development of a potential anti-cancer drug that inhibits the function of serine hydroxymethyltransferase
ReferencesReferences
</StructureSection>