Aldo-keto reductase family 1 member C3, commonly known as AKR1C3, is an enzyme. It belongs to the aldo-keto reductase superfamily, a group of over 40 known enzymes. AKR1C3 participates in various metabolic reactions. Its widespread presence in human tissues indicates broad involvement in bodily functions.
How AKR1C3 Functions as an Enzyme
AKR1C3 operates as a reductase, an enzyme that adds hydrogen atoms to specific molecules. It converts aldehydes and ketones into their corresponding alcohols. This activity relies on cofactors like NADPH, which provides the necessary hydrogen atoms.
The enzyme functions at its active site, a three-dimensional pocket where target molecules (substrates) bind. The active site contains structures like the nicotinamide ring of the NADPH cofactor and catalytic residues such as H117 and Y55. These components work together to orient the substrate correctly, allowing the enzymatic reaction to proceed efficiently.
AKR1C3 possesses a steroid binding channel and additional subpockets within its active site. “Gatekeeper” residues, like W227 and L54, influence the orientation of substrates as they enter this channel. This architecture dictates the enzyme’s ability to interact with and transform various molecules.
AKR1C3’s Role in Healthy Bodily Processes
AKR1C3 metabolizes steroid hormones, which regulate many bodily functions. It helps maintain the balance of androgens, estrogens, and progestins. For example, AKR1C3 can convert weaker steroid precursors, such as androstenedione, into more potent hormones like testosterone.
The enzyme also transforms estrone, a less active estrogen, into 17β-estradiol, a more potent form of estrogen. This conversion helps regulate estrogen levels in tissues. AKR1C3 also metabolizes progesterone, converting it into 20α-hydroxyprogesterone, a less active progestin.
Beyond steroid metabolism, AKR1C3 is involved in prostaglandin synthesis, specifically converting prostaglandin D2 (PGD2) to 11β-prostaglandin F2α (11β-PGF2α). Prostaglandins are lipid compounds that regulate inflammation and other physiological responses. The enzyme’s ability to produce 11β-PGF2α can influence cell proliferation signals.
AKR1C3’s Involvement in Disease
AKR1C3’s activity is linked to various diseases, particularly cancer. Its overexpression is frequently observed in several human tumors, including prostate and breast cancer. In these hormone-dependent cancers, AKR1C3 contributes to tumor progression by increasing the local production of potent androgens and estrogens.
The enzyme also contributes to drug resistance, especially in chemotherapy. AKR1C3 can inactivate certain chemotherapy drugs, such as doxorubicin, by metabolizing their carbonyl groups, leading to their elimination. This mechanism reduces the effectiveness of these treatments, making cancer cells more resilient to therapeutic agents.
In breast cancer, increased AKR1C3 levels have been shown to reduce doxorubicin-induced cell death. This resistance may involve the loss of the tumor suppressor PTEN and the subsequent activation of the Akt pathway, which promotes anti-apoptosis. It can also contribute to resistance to other drugs like cisplatin and gemcitabine in various cancers.
AKR1C3 is also involved in prostate cancer, particularly in the development of castration-resistant prostate cancer (CRPC). In this condition, the enzyme continues to produce androgens, such as testosterone, even after androgen-deprivation therapy. This persistent androgen synthesis fuels tumor growth and contributes to treatment failure.
New Avenues for AKR1C3 in Medicine
Given its role in disease, AKR1C3 is a potential target for therapeutic intervention. Inhibiting AKR1C3 could offer a strategy to overcome drug resistance in various cancers. Research focuses on developing specific inhibitors to block the enzyme’s activity.
Such inhibitors aim to restore sensitivity to chemotherapy drugs or modulate hormone levels in hormone-dependent cancers. For example, some nonsteroidal anti-inflammatory drugs (NSAIDs) have shown inhibitory effects on AKR1C3. Developing more selective inhibitors is an ongoing area of study, with new compounds continually discovered and evaluated.
Targeting AKR1C3 could also enhance the efficacy of existing anti-hormonal therapies. For instance, an AKR1C3 inhibitor like indomethacin has been shown to restore sensitivity to abiraterone and enzalutamide in advanced prostate cancer. This approach suggests a path toward more effective combination therapies for challenging malignancies.