KEGG   PATHWAY: hsa04918Help
hsa04918                    Pathway                                

Thyroid hormone synthesis - Homo sapiens (human)
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.
Organismal Systems; Endocrine system
BRITE hierarchy
Pathway map
hsa04918  Thyroid hormone synthesis

Ortholog table
nt06322  TRH-TSH-TH signaling
N00782  TSH-TG signaling pathway
N00783  Mutation-inactivated TSH to TSH-TG signaling pathway
N00784  Mutation-inactivated TSHR to TSH-TG signaling pathway
N00785  Mutation-inactivated PAX8 to TSH-TG signaling pathway
N00786  Transport of iodide
N00787  Mutation-inactivated NIS to transport of iodide
N00788  Mutation-inactivated PDS to transport of iodide
N00789  Mutation-inactivated TPO to iodide organification/coupling reactions
N00790  Mutation-inactivated TG to iodide organification/coupling reactions
N00791  Deiodination of MIT and DIT
N00792  Mutation-inactivated IYD to deiodination of MIT and DIT
N00793  TSH-DUOX2-TG signaling pathway
N00794  Mutation-inactivated DUOX2 to TSH-DUOX2-TG signaling pathway
N00795  DUOX2-generated H2O2 production
N00796  Mutation-inactivated DUOXA2 to DUOX2-generated H2O2 production
N00797  Mutation-activated TSHR to TSH-TG signaling pathway
N00803  Iodide organification/coupling reactions
H00250  Congenital nongoitrous hypothyroidism (CHNG)
H00251  Thyroid dyshormonogenesis
H01699  Isolated TSH deficiency
D00401  Methimazole (USP)
D00562  Propylthiouracil (JP17/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)
Other DBs
GO: 0006590
Homo sapiens (human) [GN:hsa]
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:]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:]
7270  TTF1; transcription termination factor 1 [KO:K15225]
8458  TTF2; transcription termination factor 2 [KO:K15173] [EC:3.6.4.-]
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]
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:]
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:]
476  ATP1A1; ATPase Na+/K+ transporting subunit alpha 1 [KO:K01539] [EC:]
477  ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:]
478  ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:]
480  ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:]
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:]
405753  DUOXA2; dual oxidase maturation factor 2 [KO:K17232]
257202  GPX6; glutathione peroxidase 6 [KO:K00432] [EC:]
2882  GPX7; glutathione peroxidase 7 [KO:K00432] [EC:]
2877  GPX2; glutathione peroxidase 2 [KO:K00432] [EC:]
2878  GPX3; glutathione peroxidase 3 [KO:K00432] [EC:]
2876  GPX1; glutathione peroxidase 1 [KO:K00432] [EC:]
2880  GPX5; glutathione peroxidase 5 [KO:K00432] [EC:]
493869  GPX8; glutathione peroxidase 8 (putative) [KO:K00432] [EC:]
2936  GSR; glutathione-disulfide reductase [KO:K00383] [EC:]
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]
50506  DUOX2; dual oxidase 2 [KO:K13411] [EC:1.11.1.-]
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
Ahad F, Ganie SA
Iodine, Iodine metabolism and Iodine deficiency disorders revisited.
Indian J Endocrinol Metab 14:13-7 (2010)
Gillam MP, Kopp P
Genetic defects in thyroid hormone synthesis.
Curr Opin Pediatr 13:364-72 (2001)
Rokita SE, Adler JM, McTamney PM, Watson JA Jr
Efficient use and recycling of the micronutrient iodide in mammals.
Biochimie 92:1227-35 (2010)
Massart C, Hoste C, Virion A, Ruf J, Dumont JE, Van Sande J
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.
Mol Cell Endocrinol 343:32-44 (2011)
Bizhanova A, Kopp P
Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.
Endocrinology 150:1084-90 (2009)
Fong P
Thyroid iodide efflux: a team effort?
J Physiol 589:5929-39 (2011)
Song Y, Driessens N, Costa M, De Deken X, Detours V, Corvilain B, Maenhaut C, Miot F, Van Sande J, Many MC, Dumont JE
Roles of hydrogen peroxide in thyroid physiology and disease.
J Clin Endocrinol Metab 92:3764-73 (2007)
Kohn LD, Suzuki K, Nakazato M, Royaux I, Green ED
Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte.
Trends Endocrinol Metab 12:10-6 (2001)
Marino M, McCluskey RT
Role of thyroglobulin endocytic pathways in the control of thyroid hormone release.
Am J Physiol Cell Physiol 279:C1295-306 (2000)
Rivolta CM, Targovnik HM
Molecular advances in thyroglobulin disorders.
Clin Chim Acta 374:8-24 (2006)
De La Vieja A, Dohan O, Levy O, Carrasco N
Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology.
Physiol Rev 80:1083-105 (2000)
Ohye H, Sugawara M
Dual oxidase, hydrogen peroxide and thyroid diseases.
Exp Biol Med (Maywood) 235:424-33 (2010)
Targovnik HM, Esperante SA, Rivolta CM
Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations.
Mol Cell Endocrinol 322:44-55 (2010)
Grasberger H
Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism.
Mol Cell Endocrinol 322:99-106 (2010)
Arvan P, Kim PS, Kuliawat R, Prabakaran D, Muresan Z, Yoo SE, Abu Hossain S
Intracellular protein transport to the thyrocyte plasma membrane: potential implications for thyroid physiology.
Thyroid 7:89-105 (1997)
Vono-Toniolo J, Kopp P
Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism.
Arq Bras Endocrinol Metabol 48:70-82 (2004)
Vitale G, Salvioli S, Franceschi C
Oxidative stress and the ageing endocrine system.
Nat Rev Endocrinol 9:228-40 (2013)
Calebiro D, Nikolaev VO, Lohse MJ
Imaging of persistent cAMP signaling by internalized G protein-coupled receptors.
J Mol Endocrinol 45:1-8 (2010)
Newman CM, Price A, Davies DW, Gray TA, Weetman AP
Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy.
Heart 79:121-7 (1998)
KO pathway

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