DNA-(apurinic or apyrimidinic site) lyase

In enzymology, DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase (systematic name) or DNA AP lyase (EC 4.2.99.18) is a class of enzyme that catalyzes the chemical reaction of the cleavage of the C3'-O-P bond 3' from the apurinic or apyrimidinic site in DNA via beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. In the 1970s, this class of enzyme was found to repair at apurinic or apyrimidinic DNA sites in E. coli and in mammalian cells. The major active enzymes of this class in bacteria, and specifically, E. coli is endonuclease type III, while in humans it is a Mg2+-dependent AP endonuclease, APE1. This enzyme encompasses a family of lyases that cleave carbon-oxygen bonds. In enzymology, DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase (systematic name) or DNA AP lyase (EC 4.2.99.18) is a class of enzyme that catalyzes the chemical reaction of the cleavage of the C3'-O-P bond 3' from the apurinic or apyrimidinic site in DNA via beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. In the 1970s, this class of enzyme was found to repair at apurinic or apyrimidinic DNA sites in E. coli and in mammalian cells. The major active enzymes of this class in bacteria, and specifically, E. coli is endonuclease type III, while in humans it is a Mg2+-dependent AP endonuclease, APE1. This enzyme encompasses a family of lyases that cleave carbon-oxygen bonds. Several names for DNA AP lyase include: AP lyase; AP endonuclease class I; endodeoxyribonuclease (apurinic or apyrimidinic); deoxyribonuclease (apurinic or apyrimidinic); E. coli endonuclease III; phage-T4 UV endonuclease; Micrococcus luteus UV endonuclease; AP site-DNA 5'-phosphomonoester-lyase; and X-ray endonuclease III. Since DNA AP lyase is a class of structures who have numerous target genes that encode for different variations of the enzyme, there is no one single enzyme structure that can be used as an example that encompasses all versions of the enzyme. As of March 2015, 99 structures have been solved for this class of enzymes, including 23 PDB accession codes 1BIX, 1CQG, 1CQH, 1DE8, 1DE9, 1DEW, 1E9N, 1HD7, 1N39, 1N3A, 1N3C, 1VYB, 2ABK, 2I5W, 2ISI, 2J63, 2NOB, 2NOE, 2NOF, 2NOH, 2NOI, 2NOL, and 2NOZ. APE1 is a gene that codes for DNA AP lyase in humans which binds to AP DNA loops into both the DNA major and minor grooves and binds a flipped-out AP site in a pocket that excludes DNA bases and racemized-anomer AP sites. Both the APE1 active-site geometry and a complex with cleaved AP-DNA and Mn2+ support a testable structure-based catalytic mechanism. Mn2+ stabilizes the reaction of the lyase activity. AP lyase enzymes catalyze reactions analogous to β-elimination reaction. Initially, AP hydrolyses, such as apurinic or apyrimidinic endonuclease I contain a Mg2+ active site that cleaves the DNA on the 5'-side, yielding a 5'-deoxyribosephosphate and 3'-OH. An AP site in DNA appears when the glycosylic bond that connects the purine or pyrimidine base to the deoxyribose sugar is cleaved. This reaction is referred to as depurination or depyrimidination. The sugar at the AP site is a highly unstable cyclic carboxonium ion that undergoes rapid hydrolysis to yield a diastereomeric mixture of 2-deoxy-α-D-ribose and 2-deoxy-β-D-ribose. AP lyase enzymes could be trapped on both pre-incised and unincised AP DNA by a reducing agent such as sodium borohydride. Furthermore, the catalytic mechanism of AP lyases, the β-elimination reaction, proceeds through an imine enzyme–DNA intermediate. In E. coli, DNA AP lyase (endonuclease III) helps repair oxidative damage to DNA bases by catalyzing the excision of the damaged pyrimidines and purines from ring saturation or opening from the DNA backbone. This damage can be caused by non-enzymatic hydrolysis, and/or exposure to ionizing radiation. Both UV endonuclease V from bacteriophage T4 (UV endonuclease V) and UV endonuclease III from E. coli catalyze N- glycosylase and the 3‘-abasic endonuclease reactions. Bacteriophage T4 and Micrococcus luteus UV endonucleases were actually shown not to be under the class of 'endonuclease,' but rather were β-elimination catalysts for reactions at AP sites at the C3'-O-P bond—thus, classifying them as AP lyases. Phage-T4 UV endonucleases also catalyze the reaction of the δ-reaction, nicking C5'-O-P bond at AP sites, although this reaction is slow and the enzyme should still be classified as AP lyase. This open ring allows the substitution of the correct base by other enzymes. DNA AP lyase activity is documented to have similar function in both E. Coli and in humans. A homolog of endonuclease III, human endonuclease III homolog 1, or hNTH1 functions similarly in humans as its homolog does in E. Coli. DNA damage is ubiquitous amongst all forms of life. There is an estimated 1 x 10−4 to 1 x 10−6 mutations per human gamete, which follows to finding at least one mutation at a specific locus per one million gametes. DNA is the only biologic molecule that relies solely on repair of existing molecules, and is the largest molecule that can continue to function albeit numerous mutations; thus, mutations accumulate over time. However without this repair, conditions such as UV-sensitive syndrome, xeroderma pigmentosum, and Cockayne syndrome may arise. The least severe of the three, people suffering from UV-sensitive syndrome experience UV-hypersensitivity. The syndrome arises from a mutation in the KIAA1530 protein. Unlike other severe conditions involving skin cancers and significantly reduced lifespan, this condition may result in freckles, and other skin blemishes, but does not increase likelihood of attracting a skin cancer. This condition is so rare that it has been documented to occur in seven individuals worldwide. However, it is speculated that this condition is understudied, and there are, in fact, more individuals living with the syndrome.