Advertisement

Topics

Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid.

08:00 EDT 27th March 2019 | BioPortfolio

Summary of "Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid."

Mammalian steroid 5β-reductases belong to the Aldo-Keto Reductase 1D sub-family and are essential for the formation of A-ring 5β-reduced steroids. Steroid 5β-reduction is required for the biosynthesis of bile-acids and the metabolism of all steroid hormones that contain a Δ-3-ketosteroid functionally to yield the 5β-reduced metabolites. In mammalian AKR1D enzymes the conserved catalytic tetrad found in all AKRs (Y55, H117, K84 and D50) has changed in that the conserved H117 is replaced with a glutamic acid (E120). E120 may act as a "superacid" to facilitate enolization of the Δ-ketosteroid. In addition, the absence of the bulky imidazole side chain of histidine in E120 permits the steroid to penetrate deeper into the active site so that hydride transfer can occur to the steroid C5 position. In murine steroid 5β-reductase AKR1D4, we find that there is a long-form, with an 18 amino-acid extension at the N-terminus (AKR1D4L) and a short-form (AKR1D4S), where the latter is recognized as AKR1D4 by the major data-bases. Both enzymes were purified to homogeneity and product profiling was performed. With progesterone and cortisol, AKR1D4L and AKR1D4S catalyzed smooth conversion to the 5β-dihydrosteroids. However, with Δ-androstene-3,17-dione as substrate, a mixture of products was observed which included, 5β-androstane-3,17-dione (expected) but 3α-hydroxy-5β- androstan-17-one was also formed. The latter compound was distinguished from its isomeric 3β-hydroxy-5β-androstan-17-one by forming picolinic acid derivatives followed by LC-MS. These data show that AKR1D4L and AKR1D4S also act as 3α-hydroxysteroid dehydrogenases when presented with Δ-androstene-3,17-dione and suggest that E120 alters the position the steroid to enable a correct trajectory for hydride transfer and may not act as a "superacid".

Affiliation

Journal Details

This article was published in the following journal.

Name: Chemico-biological interactions
ISSN: 1872-7786
Pages:

Links

DeepDyve research library

PubMed Articles [14375 Associated PubMed Articles listed on BioPortfolio]

AKR1D1 regulates glucocorticoid availability and glucocorticoid receptor activation in human hepatoma cells.

Steroid hormones, including glucocorticoids and androgens, have potent actions to regulate many cellular processes within the liver. The steroid A-ring reductase, 5β-reductase (AKR1D1), is predominan...

Translation from murine to human lung imaging using x-ray dark field radiography: A simulation study.

Recent studies on murine models have demonstrated the potential of dark field (DF) x-ray imaging for lung diseases. The alveolar microstructure causes small angle scattering, which is visualised in DF...

Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease.

In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the opti...

In silico and functional studies reveal novel loss-of-function variants of SRD5A2, but no variants explaining excess 5α-reductase activity.

Androgens are steroid hormones essential for human male and female development. Steroid reductases 5α (SRD5 As) are key enzymes in androgen biosynthesis. Mutations in the human SRD5 A2 are known ...

A sensitive and robust UPLC-MS/MS method for quantitation of estrogens and progestogens in human serum.

With the widespread use of sex-steroid hormones in contraceptives and hormone replacement therapy, there is an increasing need for reliable analytical methods. We report the development of a sensitive...

Clinical Trials [3903 Associated Clinical Trials listed on BioPortfolio]

Stem Cells Therapy for Corneal Blindness

This is a investigative initiated, non-comparative pilot clinical trial to ascertain the safety of application of ex-vivo cultivated limbal stem cells in human eyes for treating different ...

The Efficacy of the Nanit-Insights App in Improving Infant Sleep

The proposed study aims to examine the effectiveness of Nanit-Insights, an app-based intervention for parents who wish to improve their infant's sleep.

FCM Analysis GR in Steroid-Treatment Patients

Monitoring the GR with a GR-MoAb and FITC-Dex probes by FCM would be useful and convenient in determination GR before the steroid treatment in clinical, especially in steroid resistant sta...

Study of Efalizumab Combined With Intravitreal Ranibizumab in the Treatment of Age-Related Macular Degeneration

Efalizumab is an immunosuppressive recombinant humanized IgG1 monocolonal antibody (150 Kd) that binds to human CD11a (1) and is used for the treatment of plaque psoriasis. Efalizumab was...

Report of a New Method Used to Identify the Bacteria Present in a Human Colon Biopsy Sample

The method used for the biopsy analysis may be able to provide important insights into the complex microbial communities found in the human colon or in complex human infections. Therefore,...

Medical and Biotech [MESH] Definitions

A replication-defective murine sarcoma virus (SARCOMA VIRUSES, MURINE) capable of transforming mouse lymphoid cells and producing erythroid leukemia after superinfection with murine leukemia viruses (LEUKEMIA VIRUS, MURINE). It has also been found to transform cultured human fibroblasts, rat liver epithelial cells, and rat adrenocortical cells.

A replication-defective strain of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) capable of transforming lymphoid cells and producing a rapidly progressing lymphoid leukemia after superinfection with FRIEND MURINE LEUKEMIA VIRUS; MOLONEY MURINE LEUKEMIA VIRUS; or RAUSCHER VIRUS.

Aldo-keto reductase that functions with 5-alpha and 5-beta-steroid reductases to convert steroid hormones into the 3-alpha or 5-alpha and 3-alpha or 5-beta-tetrahydrosteroid, including 5-ALPHA-DIHYDROTESTOSTERONE to ANDROSTANE-3,17-DIOL. It also binds to BILE ACIDS. Mutations in the AKR1C2 gene are associated with Type 8 46, XY DISORDERS OF SEX DEVELOPMENT (SRXY8).

Family of retrovirus-associated DNA sequences (ras) originally isolated from Harvey (H-ras, Ha-ras, rasH) and Kirsten (K-ras, Ki-ras, rasK) murine sarcoma viruses. Ras genes are widely conserved among animal species and sequences corresponding to both H-ras and K-ras genes have been detected in human, avian, murine, and non-vertebrate genomes. The closely related N-ras gene has been detected in human neuroblastoma and sarcoma cell lines. All genes of the family have a similar exon-intron structure and each encodes a p21 protein.

Proteins found usually in the cytoplasm or nucleus that specifically bind steroid hormones and trigger changes influencing the behavior of cells. The steroid receptor-steroid hormone complex regulates the transcription of specific genes.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topic

Multiple Sclerosis MS
Multiple sclerosis (MS) is the most common disabling neurological condition affecting 100,000 young adults in the UK. The condition results from autoimmune damage to myelin, causing interference in nerve signaling. Symptoms experienced depend on the pa...


Searches Linking to this Article