Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Hyperinsulinism-Hyperammonemia Syndrome
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Disease
Created: 2013-08-01
Last Updated: 2022-12-14
Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.
References
Hyperinsulinism-Hyperammonemia Syndrome References
[Uniprot: P00367](http://www.uniprot.org/uniprot/P00367)
[OMIM: Entry 606762](http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606762)
De Lonlay P, Benelli C, Fouque F, Ganguly A, Aral B, Dionisi-Vici C, Touati G, Heinrichs C, Rabier D, Kamoun P, Robert JJ, Stanley C, Saudubray JM: Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. Pediatr Res. 2001 Sep;50(3):353-7. doi: 10.1203/00006450-200109000-00010.
Pubmed: 11518822
Glaser B, Thornton PS, Herold K, Stanley CA: Clinical and molecular heterogeneity of familial hyperinsulinism. J Pediatr. 1998 Dec;133(6):801-2.
Pubmed: 9843361
MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA: Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001 Apr;86(4):1782-7. doi: 10.1210/jcem.86.4.7414.
Pubmed: 11297618
Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M, Hayashi Y: Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. J Pediatr. 2000 Jan;136(1):69-72.
Pubmed: 10636977
Palladino AA, Stanley CA: The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0.
Pubmed: 20936362
Glutamate Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Yelamanchi SD, Jayaram S, Thomas JK, Gundimeda S, Khan AA, Singhal A, Keshava Prasad TS, Pandey A, Somani BL, Gowda H: A pathway map of glutamate metabolism. J Cell Commun Signal. 2016 Mar;10(1):69-75. doi: 10.1007/s12079-015-0315-5. Epub 2015 Dec 3.
Pubmed: 26635200
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X: The sequence of the human genome. Science. 2001 Feb 16;291(5507):1304-51. doi: 10.1126/science.1058040.
Pubmed: 11181995
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Gomez-Fabre PM, Aledo JC, Del Castillo-Olivares A, Alonso FJ, Nunez De Castro I, Campos JA, Marquez J: Molecular cloning, sequencing and expression studies of the human breast cancer cell glutaminase. Biochem J. 2000 Jan 15;345 Pt 2:365-75.
Pubmed: 10620514
Perez-Gomez C, Mates JM, Gomez-Fabre PM, del Castillo-Olivares A, Alonso FJ, Marquez J: Genomic organization and transcriptional analysis of the human l-glutaminase gene. Biochem J. 2003 Mar 15;370(Pt 3):771-84. doi: 10.1042/BJ20021445.
Pubmed: 12444921
McKnight GL, Mudri SL, Mathewes SL, Traxinger RR, Marshall S, Sheppard PO, O'Hara PJ: Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase. J Biol Chem. 1992 Dec 15;267(35):25208-12.
Pubmed: 1460020
Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. doi: 10.1038/nature03466.
Pubmed: 15815621
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17.
Pubmed: 21269460
Hinderlich S, Berger M, Schwarzkopf M, Effertz K, Reutter W: Molecular cloning and characterization of murine and human N-acetylglucosamine kinase. Eur J Biochem. 2000 Jun;267(11):3301-8. doi: 10.1046/j.1432-1327.2000.01360.x.
Pubmed: 10824116
Davidson JN, Rao GN, Niswander L, Andreano C, Tamer C, Chen KC: Organization and nucleotide sequence of the 3' end of the human CAD gene. DNA Cell Biol. 1990 Nov;9(9):667-76. doi: 10.1089/dna.1990.9.667.
Pubmed: 1979741
Sigoillot FD, Kotsis DH, Serre V, Sigoillot SM, Evans DR, Guy HI: Nuclear localization and mitogen-activated protein kinase phosphorylation of the multifunctional protein CAD. J Biol Chem. 2005 Jul 8;280(27):25611-20. doi: 10.1074/jbc.M504581200. Epub 2005 May 12.
Pubmed: 15890648
Iwahana H, Fujimura M, Ii S, Kondo M, Moritani M, Takahashi Y, Yamaoka T, Yoshimoto K, Itakura M: Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis. Biochem Biophys Res Commun. 1996 Feb 6;219(1):249-55. doi: 10.1006/bbrc.1996.0213.
Pubmed: 8619816
Finckh U, Kohlschutter A, Schafer H, Sperhake K, Colombo JP, Gal A: Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat. 1998;12(3):206-11. doi: 10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E.
Pubmed: 9711878
Funghini S, Donati MA, Pasquini E, Zammarchi E, Morrone A: Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat. 2003 Oct;22(4):340-1. doi: 10.1002/humu.9184.
Pubmed: 12955727
Aoshima T, Kajita M, Sekido Y, Kikuchi S, Yasuda I, Saheki T, Watanabe K, Shimokata K, Niwa T: Novel mutations (H337R and 238-362del) in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. Hum Hered. 2001;52(2):99-101. doi: 10.1159/000053360.
Pubmed: 11474210
Iwahana H, Oka J, Mizusawa N, Kudo E, Ii S, Yoshimoto K, Holmes EW, Itakura M: Molecular cloning of human amidophosphoribosyltransferase. Biochem Biophys Res Commun. 1993 Jan 15;190(1):192-200. doi: 10.1006/bbrc.1993.1030.
Pubmed: 8380692
Brayton KA, Chen Z, Zhou G, Nagy PL, Gavalas A, Trent JM, Deaven LL, Dixon JE, Zalkin H: Two genes for de novo purine nucleotide synthesis on human chromosome 4 are closely linked and divergently transcribed. J Biol Chem. 1994 Feb 18;269(7):5313-21.
Pubmed: 8106516
Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA: t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. Blood. 2000 Dec 15;96(13):4360-2.
Pubmed: 11110714
Hirst M, Haliday E, Nakamura J, Lou L: Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. J Biol Chem. 1994 Sep 23;269(38):23830-7.
Pubmed: 8089153
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings