| Serine dehydratase | |||||||
|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||
| Symbol | SDS | ||||||
| NCBI gene | 10993 | ||||||
| HGNC | 10691 | ||||||
| OMIM | 182128 | ||||||
| RefSeq | NM_006843 | ||||||
| UniProt | P20132 | ||||||
| Other data | |||||||
| EC number | 4.3.1.17 | ||||||
| Locus | Chr. 12q24.21 | ||||||
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Serine dehydratase orL-serine ammonia lyase (SDH) is in the β-family ofpyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structure and properties vary among species. SDH is found inyeast, bacteria, and thecytoplasm of mammalianhepatocytes. SDH catalyzes thedeamination ofL-serine to yieldpyruvate, with the release ofammonia.[1]
This enzyme has onesubstrate,L-serine, and twoproducts,pyruvate andNH3, and uses onecofactor,pyridoxal phosphate (PLP). The enzyme's main role is ingluconeogenesis in theliver'scytoplasm.[citation needed]
Serine Dehydratase is also known as:[2]
Theholoenzyme SDH contains 319residues, onePLPcofactor molecule.[1] The overall fold of themonomer is very similar to that of otherPLP-dependent enzymes of the Beta-family. The enzyme contains a largecatalyticdomain that bindsPLP and a small domain. The domains are linked by two residues 32-35 and 138-146, with the internal gap created being the space for theactive site[1]
ThePLP cofactor is positioned in between theBeta-strands 7 and 10 of the large domain and lies on the large internal gap made between small and large domain. The cofactor iscovalently bonded through aSchiff base linkage toLys41. The cofactor is sandwiched between the side chain ofPhe40 and the main chain ofAla222. Each of the polar substituents of PLP is coordinated by functional groups: thepyridinium nitrogen of PLP is hydrogen-bonded to the side chain ofCys303, the C3-hydroxyl group of PLP is hydrogen-bonded to the side chain ofAsn67, and thephosphate group of PLP is coordinated by main chain amides from the tetraglycine loop.[1][3] (Figure 3 and Figure 4).
Thereaction catalyzed by serine dehydratase follows the pattern seen by other PLP-dependent reactions. ASchiff base linkage is made and the aminoacrylate group is released which undergoes non-enzymatic hydrolytic deamination topyruvate.[4]
According to the series of assays performed by Cleland (1967), the linear rate ofpyruvate formation at variousconcentrations of inhibitors demonstrated that L-cysteine and D-serinecompetitively inhibit the enzyme SDH.[5] The reason that SDH activity isinhibited by L-cysteine is because aninorganic sulfur is created from L-Cysteine via Cystine Desulfrase and sulfur-containing groups are known to promote inhibition.[6] L-threonine competitively inhibits Serine Dehydratase as well.
Moreover, insulin is known to accelerateglycolysis and repress induction of liver serine dehydratase in adultdiabetic rats.[7] Studies have been conducted to showinsulin causes a 40-50% inhibition of the induction serine dehydratase byglucagon inhepatocytes of rats.[8] Studies have also shown thatinsulin andepinephrine inhibit Serine Dehydratase activity by inhibitingtranscription of the SDH gene in the hepatocytes.[9] Similarly, increasing levels ofglucagon, increase the activity of SDH because thishormone up-regulates the SDH enzyme. This makes sense in the context ofgluconeogenesis. The main role of SDH is to createpyruvate that can be converted into free glucose. Andglucagon gives the signal to repress gluconeogenesis and increase the amount of free glucose in the blood by releasing glycogen stores from the liver.
Homocysteine, a compound that SDH combines with Serine to createcystathionine, also noncompetitively inhibits the action of SDH. Studies have shown that homocysteine reacts with SDH's PLP coenzyme to create a complex. This complex is devoid of coenzyme activity and SDH is not able to function (See Enzyme Mechanism Section).[10] In general, homocysteine is an amino acid and metabolite ofmethionine; increased levels of homocysteine can lead tohomocystinuria(see section Disease Relevance).[11]
In general, SDH levels decrease with increasing mammalian size.[12]
SDH enzyme plays an important role in gluconeogenesis. Activity is augmented byhigh-protein diets and starvation. During periods of lowcarbohydrates, serine is converted into pyruvate via SDH. This pyruvate enters themitochondria where it can be converted intooxaloacetate, and, thus, glucose.[13]
Little is known about the properties and the function of human SDH because human liver has low SDH activity. In a study done by Yoshida and Kikuchi, routes of glycine breakdown were measured. Glycine can be converted into serine and either become pyruvate via serine dehydratase or undergooxidative cleavage intomethylene-THF,ammonia, and carbon dioxide. Results showed the secondary importance of the SDH pathway.[13][14]
SDH may be significant in the development ofhyperglycemia and tumors.
Nonketotichyperglycemia is due to the deficiency ofthreonine dehydratase, a close relative of serine dehydratase. Serine dehydratase has also been found to be absent in humancolon carcinoma and ratsarcoma. The observed enzyme imbalance in these tumors shows that an increased capacity for the synthesis of serine is coupled to its utilization fornucleotide biosynthesis as a part of the commitment tocellular replication in cancer cells. This pattern is found insarcomas andcarcinomas, and in tumors of human and rodent origin.[15]
Human and rat serine dehydratasecDNA are identical except for a 36 amino acid residue stretch. Similarities have also been shown between yeast andE. colithreonine dehydratase and human serine dehydratase. Human SDH shows sequence homology of 27% with the yeast enzyme and 27% with the E. coli enzyme.[16] Overall PLP enzymes exhibit high conservation of the active site residues.[16]