# APRT

## Overview
Adenine phosphoribosyltransferase (APRT) is a gene that encodes the enzyme adenine phosphoribosyltransferase, which is crucial in the purine salvage pathway. This enzyme catalyzes the conversion of adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP) into adenosine monophosphate (AMP), a key nucleotide for DNA and RNA synthesis and various cellular functions. The APRT protein is characterized by a complex molecular structure, including a Rossmann fold and a functional homodimer formation, which are essential for its catalytic activity and substrate specificity (Huyet2018Structural; Silva2004Three-Dimensional). Deficiencies in the APRT enzyme, due to mutations in the APRT gene, can lead to significant health issues, including the formation of kidney stones and potential kidney damage, highlighting the enzyme's importance in metabolic health and disease (Harambat2012Adenine).

## Structure
The human adenine phosphoribosyltransferase (APRT) protein exhibits a complex molecular structure that is crucial for its function in the purine salvage pathway. The primary structure of APRT consists of a sequence of amino acids that form the backbone of the protein's three-dimensional configuration. The secondary structure is characterized by a Rossmann fold, which includes a central core of five parallel beta strands flanked by several alpha helices, a common feature in type I phosphoribosyltransferases (PRTases) (Huyet2018Structural; Silva2004Three-Dimensional).

In terms of tertiary structure, APRT is organized into a functional three-dimensional shape that includes a 'hood' region, which provides substrate selectivity, and a flexible loop that typically covers the binding site, playing a role in the enzyme's catalytic mechanism (Huyet2018Structural). The quaternary structure of APRT is a parallel homodimer, where two monomers interact closely, particularly via interactions involving Arg87 from opposite monomers (Huyet2018Structural).

Specific domains within the APRT structure include the PRPP-binding motif, which is crucial for the enzyme's activity. This motif starts from Val123 and features a conserved core sequence that anchors the 5' monophosphate group of PRPP or ribonucleotides (Huyet2018Structural). No information on common post-translational modifications or splice variant isoforms is provided in the available sources.

## Function
Adenine phosphoribosyltransferase (APRT) is an enzyme encoded by the APRT gene, playing a critical role in the purine salvage pathway. This pathway is essential for recycling purines into adenosine monophosphate (AMP), a nucleotide vital for DNA and RNA synthesis and various cellular functions. APRT catalyzes the conversion of adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP) into AMP, using magnesium as a cofactor (Hidaka1987Human; O’Toole1983Human).

In healthy cells, APRT activity prevents the accumulation of adenine, which can be toxic if converted into harmful derivatives like 8-hydroxyadenine and 2,8-dihydroxyadenine by xanthine oxidase. These derivatives are poorly soluble and can lead to kidney stone formation if they precipitate in the urine (Hidaka1987Human). The enzyme is ubiquitously expressed across various tissues, underscoring its fundamental role in maintaining adequate nucleotide pools and ensuring cellular survival and proliferation (Silva2008Structural).

Deficiencies in APRT, due to mutations, result in reduced enzyme activity, leading to elevated levels of adenine and its harmful metabolites, which can cause severe renal issues (Silva2008Structural). The study of APRT, including its structure and catalytic mechanism, is significant for understanding its role in human health and potential therapeutic targets (Silva2008Structural).

## Clinical Significance
Mutations in the APRT gene, which encodes the enzyme adenine phosphoribosyltransferase, are responsible for a rare autosomal recessive disorder known as adenine phosphoribosyltransferase deficiency. This condition disrupts purine metabolism, leading to the accumulation of 2,8-dihydroxyadenine (2,8-DHA), a substance that is insoluble in urine and forms kidney stones. These stones can cause severe kidney damage, including chronic kidney disease and end-stage renal disease if not diagnosed and managed promptly (Harambat2012Adenine).

The clinical manifestations of APRT deficiency vary and can include nephrolithiasis (kidney stones), hematuria (blood in urine), urinary tract infections, and acute kidney injury. The diagnosis is often under-recognized, with some cases only identified after significant kidney damage has occurred (Harambat2012Adenine). Early diagnosis and treatment with xanthine oxidoreductase inhibitors, such as allopurinol, are crucial for preventing further kidney stone formation and potential stabilization or improvement of kidney function (Harambat2012Adenine; Balasubramaniam2014Inborn).

Pathogenic variants of the APRT gene, including missense and splice-site mutations, have been identified and are particularly prevalent in populations with a founder effect, such as those in Japan and Iceland. These mutations lead to abolished APRT enzyme function or clinical findings characteristic of the deficiency (Runolfsdottir2021Allele).

## Interactions
The human adenine phosphoribosyltransferase (hAPRT) protein engages in several critical interactions that are essential for its function and specificity. The structure of hAPRT reveals a flexible loop that plays a pivotal role in sequestering substrates from the solvent and is involved in the active site's closure during catalysis. This loop does not interact with the hood subdomain, which is crucial for base recognition and contains conserved residues that determine nucleophile affinity through hydrogen bonds and hydrophobic interactions (Silva2004Three-Dimensional). 

In the AMP-bound hAPRT structure, the carbonyl oxygen of Val25 forms a hydrogen bond with the adenine N6 atom, and Arg67 interacts directly with the adenine base. These interactions are vital for the enzyme's specificity and function. Additionally, mutations in hAPRT, such as Asp65Val, can affect its interaction with other proteins or nucleic acids by altering the binding dynamics at the PRPP β-phosphate binding site, which is crucial for the enzyme's function (Silva2004Three-Dimensional). These interactions highlight the complex nature of hAPRT's role in cellular metabolism and its sensitivity to structural changes that can impact its activity and interactions.


## References


[1. (Harambat2012Adenine) Jérôme Harambat, Guillaume Bollée, Michel Daudon, Irène Ceballos-Picot, and Albert Bensman. Adenine phosphoribosyltransferase deficiency in children. Pediatric Nephrology, 27(4):571–579, January 2012. URL: http://dx.doi.org/10.1007/s00467-011-2037-0, doi:10.1007/s00467-011-2037-0. (44 citations) 10.1007/s00467-011-2037-0](https://doi.org/10.1007/s00467-011-2037-0)

[2. (Balasubramaniam2014Inborn) Shanti Balasubramaniam, John A. Duley, and John Christodoulou. Inborn errors of purine metabolism: clinical update and therapies. Journal of Inherited Metabolic Disease, 37(5):669–686, June 2014. URL: http://dx.doi.org/10.1007/s10545-014-9731-6, doi:10.1007/s10545-014-9731-6. (61 citations) 10.1007/s10545-014-9731-6](https://doi.org/10.1007/s10545-014-9731-6)

[3. (Runolfsdottir2021Allele) Hrafnhildur L. Runolfsdottir, John A. Sayer, Olafur S. Indridason, Vidar O. Edvardsson, Brynjar O. Jensson, Gudny A. Arnadottir, Sigurjon A. Gudjonsson, Run Fridriksdottir, Hildigunnur Katrinardottir, Daniel Gudbjartsson, Unnur Thorsteinsdottir, Patrick Sulem, Kari Stefansson, and Runolfur Palsson. Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency. European Journal of Human Genetics, 29(7):1061–1070, March 2021. URL: http://dx.doi.org/10.1038/s41431-020-00805-6, doi:10.1038/s41431-020-00805-6. (5 citations) 10.1038/s41431-020-00805-6](https://doi.org/10.1038/s41431-020-00805-6)

[4. (Silva2004Three-Dimensional) Marcio Silva, Carlos Henrique Tomich de Paula Silva, Jorge Iulek, and Otavio Henrique Thiemann. Three-dimensional structure of human adenine phosphoribosyltransferase and its relation to dha-urolithiasis,. Biochemistry, 43(24):7663–7671, May 2004. URL: http://dx.doi.org/10.1021/bi0360758, doi:10.1021/bi0360758. (33 citations) 10.1021/bi0360758](https://doi.org/10.1021/bi0360758)

[5. (Hidaka1987Human) Y Hidaka, T D Palella, T E O’Toole, S A Tarlé, and W N Kelley. Human adenine phosphoribosyltransferase. identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme. Journal of Clinical Investigation, 80(5):1409–1415, November 1987. URL: http://dx.doi.org/10.1172/jci113219, doi:10.1172/jci113219. (106 citations) 10.1172/jci113219](https://doi.org/10.1172/jci113219)

[6. (Silva2008Structural) Carlos H. T. P. Silva, Marcio Silva, Jorge Iulek, and Otavio H. Thiemann. Structural complexes of human adenine phosphoribosyltransferase reveal novel features of the aprt catalytic mechanism. Journal of Biomolecular Structure and Dynamics, 25(6):589–597, June 2008. URL: http://dx.doi.org/10.1080/07391102.2008.10507205, doi:10.1080/07391102.2008.10507205. (22 citations) 10.1080/07391102.2008.10507205](https://doi.org/10.1080/07391102.2008.10507205)

[7. (O’Toole1983Human) Timothy E. O’Toole, James M. Wilson, M. Henry Gault, and William N. Kelley. Human adenine phosphoribosyltransferase: characterization from subjects with a deficiency of enzyme activity. Biochemical Genetics, 21(11–12):1121–1134, December 1983. URL: http://dx.doi.org/10.1007/BF00488464, doi:10.1007/bf00488464. (10 citations) 10.1007/BF00488464](https://doi.org/10.1007/BF00488464)

[8. (Huyet2018Structural) Jessica Huyet, Mohammad Ozeir, Marie-Claude Burgevin, Benoît Pinson, Françoise Chesney, Jean-Marc Remy, Abdul Rauf Siddiqi, Roland Lupoli, Gregory Pinon, Christelle Saint-Marc, Jean-Francois Gibert, Renaud Morales, Irène Ceballos-Picot, Robert Barouki, Bertrand Daignan-Fornier, Anne Olivier-Bandini, Franck Augé, and Pierre Nioche. Structural insights into the forward and reverse enzymatic reactions in human adenine phosphoribosyltransferase. Cell Chemical Biology, 25(6):666-676.e4, June 2018. URL: http://dx.doi.org/10.1016/j.chembiol.2018.02.011, doi:10.1016/j.chembiol.2018.02.011. (11 citations) 10.1016/j.chembiol.2018.02.011](https://doi.org/10.1016/j.chembiol.2018.02.011)