ENTRY       hsa04918                    Pathway
NAME        Thyroid hormone synthesis - Homo sapiens (human)
DESCRIPTION Thyroid hormones triiodothyronine (T3) and thyroxine (T4) are essential for normal development, growth and metabolic homeostasis in all vertebrates, and synthesized in the thyroid gland. The functional unit of the thyroid gland is the follicle, delimited by a monolayer of thyrocytes. Polarized thyrocytes surround the follicular lumen; with their basal and apical surfaces facing the bloodstream and the lumen, respectively. To synthesize thyroid hormones, thyrocytes take up iodide at their basal side and concentrate it into the lumen. They also secrete in this lumen the specialized protein thyroglobulin (TG) which serves as a store for the hormones. In the follicular lumen oxidation of iodine, iodination of tyrosines (MIT, 3-monoiodotyrosine; DIT, 3,5-diiodotyrosine) and coupling of iodotyrosines takes place on tyrosine residues in TG, resulting in T3 and T4 synthesis. Iodinated TG is resorbed through the apical membrane and degraded to form T3/T4 in lysosomes; the T3/T4 is then secreted through the basal membrane.
CLASS       Organismal Systems; Endocrine system
PATHWAY_MAP hsa04918  Thyroid hormone synthesis
NETWORK     nt06322  TRH-TSH-TH signaling
  ELEMENT   N00782  TSH-TG signaling pathway
            N00786  Transport of iodide
            N00791  Deiodination of MIT and DIT
            N00793  TSH-DUOX2-TG signaling pathway
            N00795  DUOX2-generated H2O2 production
            N00803  Iodide organification/coupling reactions
DRUG        D00401  Methimazole (USP)
            D00562  Propylthiouracil (JP18/USP/INN)
            D07231  Methylthiouracil (INN)
            D07519  Benzylthiouracil
            D07616  Carbimazole (INN)
            D09673  Tafamidis (JAN/USAN/INN)
            D09674  Tafamidis meglumine (JAN/USAN)
            D10794  Patisiran sodium (JAN)
            D11116  Patisiran (USAN/INN)
            D11916  Vutrisiran sodium (JAN)
            D11917  Vutrisiran (USAN/INN)
            D11972  Acoramidis (USAN)
            D11973  Acoramidis hydrochloride (JAN/USAN)
DBLINKS     GO: 0006590
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        7252  TSHB; thyroid stimulating hormone subunit beta [KO:K05251]
            1081  CGA; glycoprotein hormones, alpha polypeptide [KO:K08522]
            7253  TSHR; thyroid stimulating hormone receptor [KO:K04249]
            2778  GNAS; GNAS complex locus [KO:K04632]
            107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
            108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
            109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
            196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
            111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
            112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
            113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
            114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
            115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
            5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
            5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
            5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
            2776  GNAQ; G protein subunit alpha q [KO:K04634]
            23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
            5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
            5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
            5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
            5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
            5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
            5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
            7270  TTF1; transcription termination factor 1 [KO:K15225]
            8458  TTF2; transcription termination factor 2 [KO:K15173] [EC:5.6.2.-]
            7849  PAX8; paired box 8 [KO:K09293]
            1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
            1386  ATF2; activating transcription factor 2 [KO:K04450]
            468  ATF4; activating transcription factor 4 [KO:K04374]
            10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
            90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
            64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
            84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
            148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
            9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
            1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
            7038  TG; thyroglobulin [KO:K10809]
            3309  HSPA5; heat shock protein family A (Hsp70) member 5 [KO:K09490] [EC:3.6.4.10]
            7184  HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487]
            821  CANX; calnexin [KO:K08054]
            9601  PDIA4; protein disulfide isomerase family A member 4 [KO:K09582] [EC:5.3.4.1]
            432  ASGR1; asialoglycoprotein receptor 1 [KO:K10063]
            433  ASGR2; asialoglycoprotein receptor 2 [KO:K10064]
            3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
            3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
            3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
            6528  SLC5A5; solute carrier family 5 member 5 [KO:K14385]
            5172  SLC26A4; solute carrier family 26 member 4 [KO:K14702]
            7173  TPO; thyroid peroxidase [KO:K00431] [EC:1.11.1.8]
            476  ATP1A1; ATPase Na+/K+ transporting subunit alpha 1 [KO:K01539] [EC:7.2.2.13]
            477  ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:7.2.2.13]
            478  ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:7.2.2.13]
            480  ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:7.2.2.13]
            23439  ATP1B4; ATPase Na+/K+ transporting family member beta 4 [KO:K01540]
            481  ATP1B1; ATPase Na+/K+ transporting subunit beta 1 [KO:K01540]
            482  ATP1B2; ATPase Na+/K+ transporting subunit beta 2 [KO:K01540]
            483  ATP1B3; ATPase Na+/K+ transporting subunit beta 3 [KO:K01540]
            486  FXYD2; FXYD domain containing ion transport regulator 2 [KO:K01538]
            389434  IYD; iodotyrosine deiodinase [KO:K17231] [EC:1.21.1.1]
            405753  DUOXA2; dual oxidase maturation factor 2 [KO:K17232]
            53905  DUOX1; dual oxidase 1 [KO:K13411] [EC:1.6.3.1 1.11.1.-]
            50506  DUOX2; dual oxidase 2 [KO:K13411] [EC:1.6.3.1 1.11.1.-]
            257202  GPX6; glutathione peroxidase 6 [KO:K00432] [EC:1.11.1.9]
            2882  GPX7; glutathione peroxidase 7 [KO:K00432] [EC:1.11.1.9]
            2877  GPX2; glutathione peroxidase 2 [KO:K00432] [EC:1.11.1.9]
            2878  GPX3; glutathione peroxidase 3 [KO:K00432] [EC:1.11.1.9]
            2876  GPX1; glutathione peroxidase 1 [KO:K00432] [EC:1.11.1.9]
            2880  GPX5; glutathione peroxidase 5 [KO:K00432] [EC:1.11.1.9]
            493869  GPX8; glutathione peroxidase 8 (putative) [KO:K00432] [EC:1.11.1.9]
            2936  GSR; glutathione-disulfide reductase [KO:K00383] [EC:1.8.1.7]
            213  ALB; albumin [KO:K16141]
            7276  TTR; transthyretin [KO:K20731]
            6906  SERPINA7; serpin family A member 7 [KO:K20734]
            4036  LRP2; LDL receptor related protein 2 [KO:K06233]
COMPOUND    C00001  H2O
            C00005  NADPH
            C00006  NADP+
            C00007  Oxygen
            C00027  Hydrogen peroxide
            C00051  Glutathione
            C00076  Calcium cation
            C00092  D-Glucose 6-phosphate
            C00117  D-Ribose 5-phosphate
            C00127  Glutathione disulfide
            C00165  Diacylglycerol
            C00231  D-Xylulose 5-phosphate
            C00238  Potassium cation
            C00575  3',5'-Cyclic AMP
            C00708  Iodide
            C01060  3,5-Diiodo-L-tyrosine
            C01245  D-myo-Inositol 1,4,5-trisphosphate
            C01330  Sodium cation
            C01829  Thyroxine
            C02465  Triiodothyronine
            C02515  3-Iodo-L-tyrosine
REFERENCE   PMID:21448409
  AUTHORS   Ahad F, Ganie SA
  TITLE     Iodine, Iodine metabolism and Iodine deficiency disorders revisited.
  JOURNAL   Indian J Endocrinol Metab 14:13-7 (2010)
REFERENCE   PMID:11717564
  AUTHORS   Gillam MP, Kopp P
  TITLE     Genetic defects in thyroid hormone synthesis.
  JOURNAL   Curr Opin Pediatr 13:364-72 (2001)
            DOI:10.1097/00008480-200108000-00014
REFERENCE   PMID:20167242
  AUTHORS   Rokita SE, Adler JM, McTamney PM, Watson JA Jr
  TITLE     Efficient use and recycling of the micronutrient iodide in mammals.
  JOURNAL   Biochimie 92:1227-35 (2010)
            DOI:10.1016/j.biochi.2010.02.013
REFERENCE   PMID:21683758
  AUTHORS   Massart C, Hoste C, Virion A, Ruf J, Dumont JE, Van Sande J
  TITLE     Cell biology of H2O2 generation in the thyroid: investigation of the control of dual oxidases (DUOX) activity in intact ex vivo thyroid tissue and cell lines.
  JOURNAL   Mol Cell Endocrinol 343:32-44 (2011)
            DOI:10.1016/j.mce.2011.05.047
REFERENCE   PMID:19196800
  AUTHORS   Bizhanova A, Kopp P
  TITLE     Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.
  JOURNAL   Endocrinology 150:1084-90 (2009)
            DOI:10.1210/en.2008-1437
REFERENCE   PMID:21986207
  AUTHORS   Fong P
  TITLE     Thyroid iodide efflux: a team effort?
  JOURNAL   J Physiol 589:5929-39 (2011)
            DOI:10.1113/jphysiol.2011.218594
REFERENCE   PMID:17666482
  AUTHORS   Song Y, Driessens N, Costa M, De Deken X, Detours V, Corvilain B, Maenhaut C, Miot F, Van Sande J, Many MC, Dumont JE
  TITLE     Roles of hydrogen peroxide in thyroid physiology and disease.
  JOURNAL   J Clin Endocrinol Metab 92:3764-73 (2007)
            DOI:10.1210/jc.2007-0660
REFERENCE   PMID:11137035
  AUTHORS   Kohn LD, Suzuki K, Nakazato M, Royaux I, Green ED
  TITLE     Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte.
  JOURNAL   Trends Endocrinol Metab 12:10-6 (2001)
            DOI:10.1016/S1043-2760(00)00337-4
REFERENCE   PMID:11029276
  AUTHORS   Marino M, McCluskey RT
  TITLE     Role of thyroglobulin endocytic pathways in the control of thyroid hormone release.
  JOURNAL   Am J Physiol Cell Physiol 279:C1295-306 (2000)
            DOI:10.1152/ajpcell.2000.279.5.C1295
REFERENCE   PMID:16870170
  AUTHORS   Rivolta CM, Targovnik HM
  TITLE     Molecular advances in thyroglobulin disorders.
  JOURNAL   Clin Chim Acta 374:8-24 (2006)
            DOI:10.1016/j.cca.2006.05.043
REFERENCE   PMID:10893432
  AUTHORS   De La Vieja A, Dohan O, Levy O, Carrasco N
  TITLE     Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology.
  JOURNAL   Physiol Rev 80:1083-105 (2000)
            DOI:10.1152/physrev.2000.80.3.1083
REFERENCE   PMID:20407074
  AUTHORS   Ohye H, Sugawara M
  TITLE     Dual oxidase, hydrogen peroxide and thyroid diseases.
  JOURNAL   Exp Biol Med (Maywood) 235:424-33 (2010)
            DOI:10.1258/ebm.2009.009241
REFERENCE   PMID:20093166
  AUTHORS   Targovnik HM, Esperante SA, Rivolta CM
  TITLE     Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations.
  JOURNAL   Mol Cell Endocrinol 322:44-55 (2010)
            DOI:10.1016/j.mce.2010.01.009
REFERENCE   PMID:20122987
  AUTHORS   Grasberger H
  TITLE     Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism.
  JOURNAL   Mol Cell Endocrinol 322:99-106 (2010)
            DOI:10.1016/j.mce.2010.01.029
REFERENCE   PMID:9086577
  AUTHORS   Arvan P, Kim PS, Kuliawat R, Prabakaran D, Muresan Z, Yoo SE, Abu Hossain S
  TITLE     Intracellular protein transport to the thyrocyte plasma membrane: potential implications for thyroid physiology.
  JOURNAL   Thyroid 7:89-105 (1997)
            DOI:10.1089/thy.1997.7.89
REFERENCE   PMID:15611820
  AUTHORS   Vono-Toniolo J, Kopp P
  TITLE     Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism.
  JOURNAL   Arq Bras Endocrinol Metabol 48:70-82 (2004)
            DOI:10.1590/S0004-27302004000100009
REFERENCE   PMID:23438835
  AUTHORS   Vitale G, Salvioli S, Franceschi C
  TITLE     Oxidative stress and the ageing endocrine system.
  JOURNAL   Nat Rev Endocrinol 9:228-40 (2013)
            DOI:10.1038/nrendo.2013.29
REFERENCE   PMID:20378719
  AUTHORS   Calebiro D, Nikolaev VO, Lohse MJ
  TITLE     Imaging of persistent cAMP signaling by internalized G protein-coupled receptors.
  JOURNAL   J Mol Endocrinol 45:1-8 (2010)
            DOI:10.1677/JME-10-0014
REFERENCE   PMID:9538302
  AUTHORS   Newman CM, Price A, Davies DW, Gray TA, Weetman AP
  TITLE     Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy.
  JOURNAL   Heart 79:121-7 (1998)
            DOI:10.1136/hrt.79.2.121
REL_PATHWAY hsa00350  Tyrosine metabolism
            hsa00480  Glutathione metabolism
            hsa04020  Calcium signaling pathway
            hsa04142  Lysosome
            hsa04146  Peroxisome
            hsa04530  Tight junction
KO_PATHWAY  ko04918
///
