The Metabolic Basis of Inherited Disease

Stanbury, John B.; Wyngaarden, James Β.; Fredrickson, Donald S.

doi:10.1097/00000441-196611000-00048

Cited by 84 publications

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“…GMP is also derived from IMP but via xanthosine monophosphate (XMP) through the action of IMP dehydrogenase (guaB) and GMP synthetase (guaA). Xanthine and hypoxanthine thus play significant roles in purine metabolism as components of the cellular nucleotide pool.The concentrations of purine nucleotide pool components are highly regulated (11,12), with many human diseases caused by imbalances arising from genetic polymorphisms and mutations in purine metabolism (13)(14)(15)(16)(17). For example, loss of adenosine deaminase results in severe combined immunodeficiency (18), while loss of hypoxanthine-guanine phosphoribosyltransferase leads to the hyperuricemia and neurological symptoms of LeschNyhan syndrome (14), and increases in the activity of purine nucleotide metabolic enzymes, such as IMP dehydrogenase, are associated with several types of cancer (19).…”

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“…For example, loss of adenosine deaminase results in severe combined immunodeficiency (18), while loss of hypoxanthine-guanine phosphoribosyltransferase leads to the hyperuricemia and neurological symptoms of LeschNyhan syndrome (14), and increases in the activity of purine nucleotide metabolic enzymes, such as IMP dehydrogenase, are associated with several types of cancer (19). Further, genetic polymorphisms in purine metabolic enzymes are associated with the toxic side effects of thiopurine drugs (17).…”

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Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

Pang

McFaline

Burgis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

110

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Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative chemistry, and deaminase enzymes. Here we present a fourth mechanism contributing to the burden of nucleobase deamination: incorporation of hypoxanthine and xanthine into DNA and RNA caused by defects in purine nucleotide metabolism. Using Escherichia coli and Saccharomyces cerevisiae with defined mutations in purine metabolism in conjunction with analytical methods for quantifying deaminated nucleobases in DNA and RNA, we observed large increases (up to 600-fold) in hypoxanthine in both DNA and RNA in cells unable to convert IMP to XMP or AMP (IMP dehydrogenase, guaB; adenylosuccinate synthetase, purA, and ADE12), and unable to remove dITP/ITP and dXTP/XTP from the nucleotide pool (dITP/XTP pyrophosphohydrolase, rdgB and HAM1). Conversely, modest changes in xanthine levels were observed in RNA (but not DNA) from E. coli lacking purA and rdgB and the enzyme converting XMP to GMP (GMP synthetase, guaA). These observations suggest that disturbances in purine metabolism caused by known genetic polymorphisms could increase the burden of mutagenic deaminated nucleobases in DNA and interfere with gene expression and RNA function, a situation possibly exacerbated by the nitrosative stress of concurrent inflammation. The results also suggest a mechanistic basis for the pathophysiology of human inborn errors of purine nucleotide metabolism.DNA and RNA damage | mass spectrometry | nucleobase deamination | purine metabolism | DNA repair T he chemical modification of nucleobases in DNA and RNA can arise from both physiological and adventitious mechanisms at all stages of nucleic acid metabolism. This is particularly true for deaminated versions of the nucleobases. As shown in Fig. 1 for purines, nucleobase deamination in DNA and RNA leads to the formation of 2′-deoxy-and ribonucleoside forms of hypoxanthine (2′-deoxyinosine, dI; inosine, Ino) from adenine, xanthine (2′-deoxyxanthosine, dX; xanthosine, Xao) and oxanine (2′-deoxyoxanosine, dO; oxanosine, Oxo) from guanine, and uracil (2′-deoxyuridine, dU; uridine, Urd) from cytosine (1). All of these products are miscoding and mutagenic in DNA (2-4) and can interfere with RNA editing (5) and the function of noncoding RNAs (6).There are three recognized mechanisms that contribute to nucleobase deamination in DNA and RNA, the simplest of which is hydrolysis (7). A second source of nucleobase deamination is associated with the nitrosative stress caused by increases in nitric oxide-derived nitrous anhydride during inflammation (1). A third mechanism is associated with deaminase enzymes acting on RNA and DNA, with activation-induced cytidine deaminase converting cytidine to uridine during immunoglobulin diversification in B lymphocytes an...

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Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

Pang

McFaline

Burgis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

110

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“…A characteristic of Stanbury's mind was his ability and willingness to generalize concepts and to adapt to other geographical regions in the case of iodine deficiency and overpopulation, and to other organs for metabolic disorders (7). John B. Stanbury was a wonderful mentor and trained most South American thyroidologists and quite a few Europeans.…”

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confidence: 99%

John B. Stanbury (May 15, 1915–July 6, 2015)

2015

Thyroid

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John B. Stanbury died in his sleep on July 6, 2015, in Westwood, MA, seven weeks after his 100th birthday. He was born in Clinton, NC, and went to college at Duke and medical school at Harvard. He married Jean Cook in January 1945 while in the Navy, in which he served during World War II, and raised a family of five in Chestnut Hill, MA. He is survived by Jean, his wife of 70 years, four children ( John Jr, Martha, Sarah Stanbury Smith, and David), nine grandchildren, and two great-grandchildren, and was pre-deceased by his youngest daughter, Pamela. Truly both a southern gentleman and a Boston Brahman, John led by discussion and example, and avoided arguments and conflicts. Above all, he loved a family gathering, especially on Isle au Haut, ME. He was an avid tennis player, beekeeper, and gardener.John became chief resident at the Massachusetts General Hospital (MGH), and his admiration for Fuller Albright influenced his choice for endocrinology. He commenced his own career in medical practice, teaching, and endocrine research when he became Chief of the Thyroid Unit at the MGH in 1949. Teaching was focused in the Thyroid Clinic where trainees and older staff members, including John, saw patients each day. But the main teaching event was the clinic held each Tuesday afternoon, at which several patients were presented in person, and then examined by each of the attendings. Often visitors from clinics around the world were present as well. The discussions that followed by members of medicine, surgery, pathology, and radiology departments were sharp, patient-focused, full of pearls, and provided all present with a living textbook of clinical practice. This model has been emulated in many teaching institutions around the country.The research environment in the Thyroid Unit was strong at this time, with Jacob Lerman studying immunity to thyroglobulin, Farah Maloof investigating the metabolism of thioureas, and a partnership between Karl Compton, Robley Evans, and Arthur Roberts at the Massachusetts Institute of Technology (MIT), and Saul Hertz, James Howard Means, and Earle Chapman at MGH using the just developed tool of radioactive isotopes of iodine for studying the metabolism of iodine in the thyroid gland. Studies on iodine metabolism in animals were quickly followed by investigations in man, and the first treatment of Graves' disease in 1941. These techniques were soon extended by Rulon Rawson for use in thyroid cancer. The idea of studying endemic goiter using this new technology led John

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“…This gene encodes a muscle-specific isoform of the regulatory 7 subunit of AMP-activated protein kinase. Interestingly is the fact that the comparative sequence analysis (27,67). Myotonia congenita is a very rare and nonprogressive disorder of many breeds, including the Thoroughbred, Quarterhorse and Swedish 'half-blood'.…”

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confidence: 99%