| 词条 | Adenine phosphoribosyltransferase |
| 释义 |
FunctionAPRTase catalyzes the following reaction in the purine nucleotide salvage pathway: Adenine + Phosphoribosyl Pyrophosphate (PRPP) → Adenylate (AMP) + Pyrophosphate (PPi) In organisms that can synthesize purines de novo, the nucleotide salvage pathway provides an alternative that is energetically more efficient. It can salvage adenine from the polyamine biosynthetic pathway or from dietary sources of purines.[4] Although APRTase is functionally redundant in these organisms, it becomes more important during periods of rapid growth, such as embryogenesis and tumor growth.[6] It is constitutively expressed in all mammalian tissue.[7] In protozoan parasites, the nucleotide salvage pathway provides the sole means for nucleotide synthesis. Since the consequences of APRTase deficiency in humans is comparatively mild and treatable, it may be possible to treat certain parasitic infections by targeting APRTase function.[5] In plants, as in other organisms, ARPTase functions primarily for the synthesis of adenylate. It has the unique ability to metabolize cytokinins—a plant hormone that can exist as a base, nucleotide, or nucleoside—into adenylate nucleotides.[6] APRT is functionally related to hypoxanthine-guanine phosphoribosyltransferase (HPRT). StructureAPRTase is a homodimer, with 179 amino acid residues per monomer. Each monomer contains the following regions:
The core is highly conserved across many PRTases. The hood, which contains the adenine binding site, has more variability within the family of enzymes. A 13-residue motif comprises the PRPP binding region and involves two adjacent acidic residues and at least one surrounding hydrophobic residue.[7] The enzyme's specificity for adenine involves hydrophobic residues Ala131 and Leu159 in the core domain. In humans, two residues in the hood domain hydrogen bond with the purine for further specificity: Val25 with the hydrogens on N6, and Arg27 with N1. Although the flexible loop does not interact with the hood during purine recognition, it is thought to close over the active site and sequester the reaction from solvents.[8] Most research on APRTase reports that Mg2+ is essential for phosphoribosyl transfer, and this is conserved across Type I PRTases.[6] However, a recent effort to resolve the structure of human APRTase was unable to locate a single site for Mg2+, but did find evidence to suggest a Cl− atom near Trp98. Despite the difficulty of placing Mg2+, it is generally accepted that the catalytic mechanism is dependent on this ion.[4] MechanismAPRTase proceeds via a bi bi ordered sequential mechanism, involving the formation of a ternary complex. The enzyme first binds PRPP, followed by adenine. After the phosphoribosyl transfer occurs, pyrophosphate leaves first, followed by AMP. Kinetic studies indicate that the phosphoribosyl transfer is relatively fast, while the product release (particularly the release of AMP) is rate-limiting.[9] In human APRTase, it is thought that adenine's N9 proton is abstracted by Glu104 to form an oxacarbenium transition state. This functions as the nucleophile to attack the anomeric carbon of PRPP, forming AMP and displacing pyrophosphate from PRPP. The mechanism of APRTase is generally consistent with that of other PRTases, which conserve the function of displacing PRPP's α-1-pyrophosphate using a nitrogen nucleophile, in either an SN1 or SN2 attack.[4] DeficiencyWhen APRTase has reduced or nonexistent activity, adenine accumulates from other pathways. It is degraded by xanthine dehydrogenase to 2,8-dihydroxyadenine (DHA). Although DHA is protein-bound in plasma, it has poor solubility in urine and gradually precipitates in kidney tubules, leading to the formation of kidney stones (urolithiasis). If left untreated, the condition can eventually produce kidney failure.[3] ARPTase deficiency was first diagnosed in the UK in 1976. Since then, two categories of APRTase deficiency have been defined in humans.[10] Type I deficiency results in a complete loss of APRTase activity and can occur in patients that are homozygous or compound heterozygous for various mutations.[11] Sequencing has revealed many different mutations that can account for Type 1, including missense mutations, nonsense mutations, a duplicated set of 4 base pairs in exon 3,[12] and a single thymine insertion in intron 4.[13] These mutations cause effects that are clustered into three main areas: in the binding of PRPP's β-phosphate, in the binding of PRPP's 5'-phosphate, and in the segment of the flexible loop that closes over the active site during catalysis [8] Type I deficiency has been observed in various ethnic groups but studied predominately among White populations.[13] Type II deficiency causes APRTase to have a reduced affinity for PRPP, resulting in a tenfold increase in the KM value.[4] It has been observed and studied primarily in Japan.[13] A diagnosis of APRTase deficiency can be made by analyzing kidney stones, measuring DHA concentrations in urine, or analyzing APRTase activity in erythrocytes. It is treatable with regular doses of allopurinol or febuxostat, which inhibit xanthine dehydrogenase activity to prevent the accumulation and precipitation of DHA.[14] The condition can also be attenuated with a low-purine diet and high fluid intake.[10] References1. ^{{cite journal | vauthors = Valaperta R, Rizzo V, Lombardi F, Verdelli C, Piccoli M, Ghiroldi A, Creo P, Colombo A, Valisi M, Margiotta E, Panella R, Costa E | title = Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation | journal = BMC Nephrology | volume = 15 | pages = 102 | date = 1 July 2014 | pmid = 24986359 | doi = 10.1186/1471-2369-15-102 | pmc=4094445}} 2. ^{{cite journal | vauthors = Sarver AE, Wang CC | title = The adenine phosphoribosyltransferase from Giardia lamblia has a unique reaction mechanism and unusual substrate binding properties | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39973–80 | date = Oct 2002 | pmid = 12171924 | doi = 10.1074/jbc.M205595200 }} 3. ^1 {{cite journal | vauthors = Shi W, Tanaka KS, Crother TR, Taylor MW, Almo SC, Schramm VL | title = Structural analysis of adenine phosphoribosyltransferase from Saccharomyces cerevisiae | journal = Biochemistry | volume = 40 | issue = 36 | pages = 10800–9 | date = Sep 2001 | pmid = 11535055 | doi=10.1021/bi010465h}} 4. ^1 2 3 4 {{cite journal | vauthors = Silva CH, Silva M, Iulek J, Thiemann OH | title = Structural complexes of human adenine phosphoribosyltransferase reveal novel features of the APRT catalytic mechanism | journal = Journal of Biomolecular Structure & Dynamics | volume = 25 | issue = 6 | pages = 589–97 | date = Jun 2008 | pmid = 18399692 | doi = 10.1080/07391102.2008.10507205 }} 5. ^{{cite journal | vauthors = Shi W, Sarver AE, Wang CC, Tanaka KS, Almo SC, Schramm VL | title = Closed site complexes of adenine phosphoribosyltransferase from Giardia lamblia reveal a mechanism of ribosyl migration | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39981–8 | date = Oct 2002 | pmid = 12171925 | doi = 10.1074/jbc.M205596200 }} 6. ^1 {{cite journal | vauthors = Allen M, Qin W, Moreau F, Moffatt B | title = Adenine phosphoribosyltransferase isoforms of Arabidopsis and their potential contributions to adenine and cytokinin metabolism | journal = Physiologia Plantarum | volume = 115 | issue = 1 | pages = 56–68 | date = May 2002 | pmid = 12010467 | doi=10.1034/j.1399-3054.2002.1150106.x}} 7. ^{{cite journal | vauthors = Liu Q, Hirono S, Moriguchi I | title = Quantitative structure-activity relationships for calmodulin inhibitors | journal = Chemical & Pharmaceutical Bulletin | volume = 38 | issue = 8 | pages = 2184–9 | date = Aug 1990 | pmid = 2279281 | doi=10.1248/cpb.38.2184}} 8. ^1 2 3 {{cite journal | vauthors = Silva M, Silva CH, Iulek J, Thiemann OH | title = Three-dimensional structure of human adenine phosphoribosyltransferase and its relation to DHA-urolithiasis | journal = Biochemistry | volume = 43 | issue = 24 | pages = 7663–71 | date = Jun 2004 | pmid = 15196008 | doi = 10.1021/bi0360758 }} 9. ^1 {{cite journal | vauthors = Bashor C, Denu JM, Brennan RG, Ullman B | title = Kinetic mechanism of adenine phosphoribosyltransferase from Leishmania donovani | journal = Biochemistry | volume = 41 | issue = 12 | pages = 4020–31 | date = Mar 2002 | pmid = 11900545 | doi=10.1021/bi0158730}} 10. ^1 {{cite journal | vauthors = Cassidy MJ, McCulloch T, Fairbanks LD, Simmonds HA | title = Diagnosis of adenine phosphoribosyltransferase deficiency as the underlying cause of renal failure in a renal transplant recipient | journal = Nephrology, Dialysis, Transplantation | volume = 19 | issue = 3 | pages = 736–8 | date = Mar 2004 | pmid = 14767036 | doi=10.1093/ndt/gfg562}} 11. ^{{cite journal | vauthors = Bollée G, Harambat J, Bensman A, Knebelmann B, Daudon M, Ceballos-Picot I | title = Adenine phosphoribosyltransferase deficiency | journal = Clinical Journal of the American Society of Nephrology | volume = 7 | issue = 9 | pages = 1521–7 | date = Sep 2012 | pmid = 22700886 | doi = 10.2215/CJN.02320312 }} 12. ^{{cite journal | vauthors = Kamatani N, Hakoda M, Otsuka S, Yoshikawa H, Kashiwazaki S | title = Only three mutations account for almost all defective alleles causing adenine phosphoribosyltransferase deficiency in Japanese patients | journal = The Journal of Clinical Investigation | volume = 90 | issue = 1 | pages = 130–5 | date = Jul 1992 | pmid = 1353080 | doi = 10.1172/JCI115825 | pmc=443071}} 13. ^1 2 {{cite journal | vauthors = Bollée G, Dollinger C, Boutaud L, Guillemot D, Bensman A, Harambat J, Deteix P, Daudon M, Knebelmann B, Ceballos-Picot I | title = Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency | journal = Journal of the American Society of Nephrology | volume = 21 | issue = 4 | pages = 679–88 | date = Apr 2010 | pmid = 20150536 | doi = 10.1681/ASN.2009080808 | pmc=2844298}} 14. ^{{cite journal | vauthors = Edvardsson VO, Palsson R, Sahota A | veditors = Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K | journal = SourceGeneReviews® [Internet] | title = Adenine Phosphoribosyltransferase Deficiency | date = 1993 | pmid = 22934314 }} Further reading{{refbegin|33em}}
External links
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