Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differentiation and biogenesis of mitochondria in brown adipose tissue (BAT) was studied in situ and in cell culture by Western blotting, enzyme activity measurements, [35S]methionine incorporation and immunofluorescence microscopy. In different rodent species the perinatal development of BAT thermogenic function resulted from the formation of thermogenic mitochondria which replaced the preexisting nonthermogenic mitochondria. Their biogenesis was characterized by the sudden appearance and rapid increase of the uncoupling protein (UCP), increase of cytochrome oxidase (COX) and decrease of H(+)-ATPase. In primary cell culture, differentiation of precursor cells from mouse BAT to typical multilocular adipocytes was accompanied by increasing content of COX and H(+)-ATPase. A selective synthesis of UCP was induced by activation of beta-adrenergic receptors or by elevated levels of cellular cAMP. UCP was quantitatively incorporated into mitochondria and within 24 h after stimulation reached near physiological concentration. Both in situ and in cell culture, the conditions enabling the expression of UCP gene were accompanied by activation of intracellular thyroxine 5'-deiodinase.
 ...
PMID:Differentiation of brown adipose tissue and biogenesis of thermogenic mitochondria in situ and in cell culture. 216 11

Recent studies have shown that approximately 75% of the nuclear 3,5,3'-triiodothyronine (T(3)) present in adult rat cerebral cortex (Cx) derives from 5'-deiodination of thyroxine (T(4)) within this tissue. The activity of iodothyronine 5'-deiodinase (I 5'D), the enzyme catalyzing T(4) to T(3) conversion, increases rapidly after thyroidectomy, suggesting that this could be a compensatory response to hypothyroxinemia. To evaluate this possibility during the period of central nervous system maturation, we studied several thyroid hormone-responsive enzymes (aspartic transaminase [AT], succinic dehydrogenase [S.D.], and Na/K ATPase) in the Cx of 2-, 3-, and 4-wk-old rats. The rats were made congenitally hypothyroid by placing 1, 2, 5, and 20 mg methimazole (MMI) in 100 ml of the mothers' drinking water from day 16 of gestation throughout the nursing period and to the litters after weaning. In addition, serum thyroid hormones, I 5'D, and, in some experiments, in vivo T(4) to T(3) conversion in Cx were measured in the same pups. Serum T(4) concentrations varied from <1 to 40 ng/ml and were generally inversely related to maternal MMI dose. Serum T(3) was less affected by MMI than was T(4). At 2 wk, decreases in AT, S.D., and ATPase were present in the 20-mg-MMI group but not in the 5-mg-MMI pups despite low serum T(4) (<10 ng/ml) in the latter. At 3 and 4 wk, both 5- and 20-mg-MMI groups had significant reductions in these cortical enzymes despite a normal serum T(3) in the 5-mg-MMI rats. Cortical I 5'D activity was 10-fold the control value in 5- and 20-mg-MMI animals at 2 wk but increased only three- to fivefold at 3 and 4 wk. I 5'D correlated inversely with serum T(4) (r >/= 0.96) at all ages, but the less marked elevation of this enzyme in 3- and 4-wk-old pups was not accompanied by an increase in serum T(4). Serum T(3) increased or remained the same between 2 and 3 wk. These results suggested that the 10-fold increase in I 5'D at 2 wk protected the 5-mg-MMI group from tissue hypothyroidism, but that the three- to fivefold increase at 3 and 4 wk could not. Injection of approximately 250 ng T(4)/100 g body weight to 2-wk-old, 20-mg-MMI pups (one-sixth the normal T(4) production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T(3) and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T(3) increment and no change in AT in euthyroid controls. The larger increment in T(3) of the 20-mg-MMI pups was due in great part to increased fractional T(4) to T(3) conversion. Although the latter resulted in greater serum T(3) concentrations, three-fourths of the newly formed T(3) in the cortex was generated in situ, and it was blocked by iopanoic acid as was the increase in AT. We conclude that 70-80% of the T(3) in the Cx of the neonatal rat is produced locally. Serum T(4) appears to serve both as a precursor for T(3) and as a critical signal for increases in cortical I 5'D. The increased I 5'D can result in normal or near-normal cerebrocortical T(3) concentrations despite marked reductions in serum T(4). This mechanism seems to be particularly effective around 2 wk of age when many thyroid-hormone-dependent maturational changes occur in the rat Cx.
 ...
PMID:Comparison of iodothyronine 5'-deiodinase and other thyroid-hormone-dependent enzyme activities in the cerebral cortex of hypothyroid neonatal rat. Evidence for adaptation to hypothyroidism. 621 29

We have examined iodothyronine deiodination in subcellular fractions of cerebral cortex obtained from hypothyroid rats. Enzymatic activities were measured at 37 degrees C in the presence of 20 mM dithiothreitol with 125I-labeled T4 and 125I-labeled rT3 as substrates for 5'-deiodination and 131I-labeled T3 as the substrate for the 5-deiodinase. Reaction products were separated by descending paper and/or ion-exchange chromatography. Cerebral cortex subcellular fractions were also characterized by marker enzyme analysis and electron microscopy. Under optimal reaction conditions more than 80% of the 5'-deiodinase was recovered after fractionation. Both 5'-deiodinase and (Na+ + K+)-ATPase showed similar subcellular distributions and were enriched approx. 3-fold in the easily sedimenting membrane fraction and nerve terminal plasma membranes. Crude microsomal membranes (6 X 10(6) g X min pellet) also showed 2-fold enrichment of these enzymes. Nuclei and isolated mitochondria were devoid of deiodinating activity. T4 and T3 5-deiodinating activity was absent in the easily sedimenting membranes and present but not enriched in particulate fractions containing microsomal membranes. These data suggest that iodothyronine 5'-deiodinase is associated with plasma membrane fractions in the cerebral cortex.
 ...
PMID:Subcellular distribution of iodothyronine 5'-deiodinase in cerebral cortex from hypothyroid rats. 713 1

Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T(3)-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1(-/-)) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T(3)-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1(-/-) and wild-type mice (SRC-1(+/+)). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. L-T(3) was injected ip for the last 4 d in one group (PTU+T(3) group), and another group (PTU group) received only vehicle. Levels of mRNAs for T(3)-responsive genes were determined by Northern blotting: GH and TSH beta in pituitary; type 1 iodothyronine 5'-deiodinase, spot 14 (S14), and malic enzyme in liver; and sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy chain alpha and beta in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured. Hypothyroidism produced a comparable increase in TSH beta mRNA in both genotypes, but its suppression by L-T(3) was attenuated in SRC-1(-/-) mice. In contrast, hypothyroidism failed to reduce S14 mRNA levels in SRC-1(-/-) mice. As a consequence, the response to L-T(3) was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T(3)-responsive genes examined. Of the four serum parameters, the T(3)-mediated decrease in TSH and changes in AP were attenuated in SRC-1(-/-) mice. We conclude that SRC-1 deficiency altered the expression of only some of the T(3)-responsive genes. SRC-1 appears to be involved not only in transcriptional activation by liganded TRs, but also in the suppression by liganded or unliganded TRs. Some of the effects of SRC-1 may be TR isoform specific.
 ...
PMID:Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T(3)-regulated transcription of genes in vivo. 1189 91

The type II iodothyronine deiodinase (D2) is a type I endoplasmic reticulum (ER)-resident thioredoxin fold-containing selenoprotein that activates thyroid hormone. D2 is inactivated by ER-associated ubiquitination and can be reactivated by two ubiquitin-specific peptidase-class D2-interacting deubiquitinases (DUBs). Here, we used D2-expressing cell models to define that D2 ubiquitination (UbD2) occurs via K48-linked ubiquitin chains and that exposure to its natural substrate, T4, accelerates UbD2 formation and retrotranslocation to the cytoplasm via interaction with the p97-ATPase complex. D2 retrotranslocation also includes deubiquitination by the p97-associated DUB Ataxin-3 (Atx3). Inhibiting Atx3 with eeyarestatin-I did not affect D2:p97 binding but decreased UbD2 retrotranslocation and caused ER accumulation of high-molecular weight UbD2 bands possibly by interfering with the D2-ubiquitin-specific peptidases binding. Once in the cytosol, D2 is delivered to the proteasomes as evidenced by coprecipitation with 19S proteasome subunit S5a and increased colocalization with the 20S proteasome. We conclude that interaction between UbD2 and p97/Atx3 mediates retranslocation of UbD2 to the cytoplasm for terminal degradation in the proteasomes, a pathway that is accelerated by exposure to T4.
...
PMID:The type II deiodinase is retrotranslocated to the cytoplasm and proteasomes via p97/Atx3 complex. 2419 52