Ask a Biochemist anything! Part Deux: The Androgen Receptor

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    Ask a Biochemist anything! Part Deux: The Androgen Receptor


    I'd prefer to multi-post this to get more viewers but I don't want to get flamed, Ill repost this in the anabolics forum and just remote them back here.

    1. I want as many questions as possible
    2. I don't know where this thread belongs.

    Mods can relocate or delete as they wish.

    I am currently doing a literature review of the androgen receptor for undisclosed purposes. While the information is fresh in my head and while I am still seeking out more, people are more than welcome to ask me ANYTHING that involves the androgen receptor, as technical or as non-technical as they want. I might know off hand, if I don't I'll look it up. More information for me. I'll attempt to provide the source with every answer I give as well if you want.

    Fire!!

    Regards

    Howabout I give you guys some help!

    Here are some bullets I am accumulating, It will grow longer and longer, but it might be a basis for some questions!

    Anything you ever wanted to know (and likely more) about the androgen receptor (this will get filled in as I have the time)


    Androgen Receptor:

    Intro:

    -Member of the steroid and nuclear receptor superfamily (>100 members)
    -Only 5 vertebrate steroid receptors are known
    -Estrogen (two types)
    -Alpha and Beta subtypes
    -Progesterone
    -Androgen
    -only one androgen receptor gene found in humans
    -Glucocorticoid
    -Mineralocorticoid

    -Androgen receptor gene:

    - >90kb and codes for a protein 919 AA with 3 major functional domains:
    -N-Terminal Domain (NTD)
    -Modulatory function encoded by exon 1
    -DNA binding domain (DBD)
    -Exons 2 and 3
    -Ligand Binding Domain (LBD)
    -Encoded by 5 exons
    -Hinge region between DNA binding and Ligand Binding domains
    -Two transactivation functions
    -N-Terminal activation function (AF1)
    -Constitutive in truncated receptor (lacking LBD)
    -Sequence not conserved compared to other steroid receptors
    -C-Terminal activation function (AF2)
    -Ligand-dependant (conserved sequence) in regard to charge-clamp residues

    -Androgen receptor activation:

    -Soluble, complexed with heat shot proteins, acts as an intracellular transcription factor

    -Androgen binds causing conformational changes

    -Agonist binding induces conformational change that allows for activation of AF2 that is crucial for co
    regulator recruitment (due to a LxxLL motif that co-regulators bind to) and N/C terminus interaction that
    may further stabilize the agonist-bound ligand-binding domain.

    -DHT-bound AR prefers the binding of FxxLF motifs to that of LxxLL, suggesting that N/C interaction is
    preferred over co-activator recruitment (FxxLF competes for AF2 domain)

    -HSP dissociates and transformed AR undergoes dimerization, phosphorylation, and then translocation to
    the nucleus. Mediated by the nuclear localization signal.

    -The translocated receptor binds to the androgen response element (promoter or enhancer of AR gene
    targets)

    -Co-activators and co-repressors are also involved; the ligand-binding domain mediates
    -Both steroidal and non-steroidal compounds may interact with the AR
    -May agonize (activate transcription)
    -Antagonize (inhibit transcription)

    -Nongenomic pathway of AR <--- To be further developed

    -AR responds to BOTH androgen AND signal transduction pathways

    -has been reported in oocytes, skeletal muscle, osteoblasts, and prostate cancer cells. (Distinguished due to interaction with plasma membrane-associated signaling pathways)

    -AR is most expressed in androgen target tissues:

    -Prostate
    -Skeletal muscle
    -Liver
    -Central Nervous system
    - Epididymis (duct behind testes) (most highly expressed)
    - Adrenal Gland (cool!) (Most highly expressed)

    -Tissue uptake efficiency and selectivity of different ligands seemed to be related to their binding affinity to AR and their resistance to metabolism

    Post Translational Modification of the AR:

    There are 23 known sites of direct androgen receptor post-translational modification and greater than 80% of this modification sites affect transcriptional activity in some way. While others my concurrently affect stability, growth ?, and localization.
    Modifications include
    -Phosphorylation (mostly)
    -Acetylation
    -Methylation
    -SUMOylation
    -Ubiquitination

    -Dominating hypothesis regarding phosphorylation is that phosphorylation INCREASES as androgrens bind, as
    conformational changes expose phosphorylation sites.

    -Phosphorylation is hypothesized to affect AR activity by increasing or decreasing protein interactions that occur
    proximal to the phosphosite.

    -phosphosites have been observed in all 3 main domains of the AR as well as the AFI (hormone independent
    coactivation domain) and AF2 (Hormone dependent)

    -Some sites may be constitutively phosphorylated

    -Some sites may be phosphorylated or de-phosphorylated in conjunction with androgen binding indicating
    there might be some links.

    -Phosphorylation is both dependent on location and CAUSING translocation (likely)

    -mutants at phosphorylation sites change transcriptional and translocational activity

    -Very interesting, the androgen receptor can be activated WITHOUT the binding of a ligand in certain kinase cascades or at least, sensitize the AR to lower levels of androgen.

    -Goal(s) and Missing links

    -Developing compounds that can separate the androgenic and anabolic effects of typical AR ligand. Previously thought impossible, due to the genes that the AR governs and the reliance on a SINGLE androgen receptor.
    Androgenic- prostate, seminal vesicle, testes (et al)
    Anabolic- Nitrogen retaining effects in muscle and bone

    -No crystal structure of full-length receptor

    -Preference of the AR for N/C terminus interaction for drug targets (opposite of other steroid receptors)
    -N/C interaction promotes transcription. A weaker binding compound might favor the AF2 domain to interact
    with other peptides besides the AR due to different conformations.
    -Structural basis for non-genomic interactions is not clear

    -Separation of the genomic and nongenomic functions of steroid receptors unspecific ligands was proposed as a new strategy to achieve tissue selectivity. Structural features that determine this have not been determined.

    -Crystal structures of the ligand bound AR exist for both testosterone and DHT, but there is little observable difference, this is strange considering the ridiculous differences is causes gene expression in the prostate.

    -How do the post-translational modifications of the receptor affect the transcriptional activities? Is the post-translational modification tissue dependent? If so does this cause the differential affects of DHT in the sex organs?

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    Does LCLT increase androgen receptor density?
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    Quote Originally Posted by MAxximal View Post
    Does LCLT increase androgen receptor density?
    According to this paper, it increases density post exercises (in skeletal muscle). Whether or not this is beneficial in the long run, meh. There is a chance in increases it in the prostate as well. But I don't know for sure. I might thumb through to see if I can find something.

    Kraemer, W. J., et. al., Androgenic Responses to Resistance Exercise: Effects of Feeding and L-Carnitine. Medicine and Science in Sports and Exercise v. 38 no. 7 (July 2006) p. 1288-96

    I don't think this paper is new to anybody though.
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    As an older male weight lifter, almost 60, what additions to regimen will make a difference in maintaining musculature and youthful appearance? This person has lifted for over 20 years and doesnt care to cycle anything except supplements.
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    Quote Originally Posted by Knowbull View Post
    As an older male weight lifter, almost 60, what additions to regimen will make a difference in maintaining musculature and youthful appearance? This person has lifted for over 20 years and doesnt care to cycle anything except supplements.
    As somebody with your amount of 'wisdom' there are two issues.

    Not only is your total testosterone lower, your amount of free testosterone is also decreased because the body upregulates proteins responsible for binding your testosterone up. Then what little testosterone you do have, a portion of that is converted to dihydrotestosterone, which is really only active in places you DON'T want it to be (scalp, prostate etc)

    I'd look at supplements to increase your (free) testosterone and stuff that will keep DHT conversion at bay. I'll let you do the deciding on what to take, as this is just a conceptual matter. At your age, there are other things besides androgens they may help in musculature and youthful appearance.

    But in all honesty, nothing beats a LOT of GOOD sleep and LOW STRESS.

    Nothing cans supplement for that.
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    Quote Originally Posted by TheProfessor View Post
    As somebody with your amount of 'wisdom' there are two issues.

    Not only is your total testosterone lower, your amount of free testosterone is also decreased because the body upregulates proteins responsible for binding your testosterone up. Then what little testosterone you do have, a portion of that is converted to dihydrotestosterone, which is really only active in places you DON'T want it to be (scalp, prostate etc)

    I'd look at supplements to increase your (free) testosterone and stuff that will keep DHT conversion at bay. I'll let you do the deciding on what to take, as this is just a conceptual matter. At your age, there are other things besides androgens they may help in musculature and youthful appearance.

    But in all honesty, nothing beats a LOT of GOOD sleep and LOW STRESS.

    Nothing cans supplement for that.
    Okay Prof, can you be a little more specific as to what supplements? What would you take? Thanks
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    Quote Originally Posted by Knowbull View Post
    Okay Prof, can you be a little more specific as to what supplements? What would you take? Thanks
    I PM'ed you.
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    Quote Originally Posted by TheProfessor View Post
    I PM'ed you.
    you can PM me too to know what supplements are?
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    subbed.. Looks interesting!
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    I posted a quick outline of some general knowledge, I'll keep filling it in as I get time. Too bad none of my formatting was saved when I reposted it. It may spark some questions people have.
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    This might be a horribly generic question to ask, but here it goes anyway. What supplements have you come across lately that may downregulate the AR, inhibit binding to the AR, or otherwise negatively affect its activity? Any amount of depth in your answer is greatly appreciated!
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    I have done a good bit of reading about SARMS yet I still feel that I don't fully understand their interaction with the androgen receptor. And I am also curious what type of negative impact they might have on the androgen receptors post cycle. I'm sorry if these questions are obvious to most people but when I read some of the scientific paperwork behind SARMS I'm kinda left scratching my head.
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    Quote Originally Posted by LikeMike View Post
    I have done a good bit of reading about SARMS yet I still feel that I don't fully understand their interaction with the androgen receptor. And I am also curious what type of negative impact they might have on the androgen receptors post cycle. I'm sorry if these questions are obvious to most people but when I read some of the scientific paperwork behind SARMS I'm kinda left scratching my head.
    Sarms bind with the androgen receptor but have (supposedly) less interaction with the sex organs that express the androgen receptor. This is because sex organs also express 5a-reductase, which converts testosterone to DHT. Relieving some of the deleterious affects associated with androgen supplementation.

    this is the GOAL of SARMS. Not what is actually happening.

    More to come later.
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    Subbed,

    To save you from getting PM'd spammed can you post that supplement list? (The Supplement list you PM'd to a member earlier? )
    RecoverBro ELITE
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    Quote Originally Posted by Torobestia View Post
    This might be a horribly generic question to ask, but here it goes anyway. What supplements have you come across lately that may downregulate the AR, inhibit binding to the AR, or otherwise negatively affect its activity? Any amount of depth in your answer is greatly appreciated!
    1. You are hard pressed to downregulate any receptor, and even so, it would be very temporary.

    2. I can't think of any androgen receptor antagonists off hand that are sold. Especially ones over the counter. If there were, it would (arbitrarily) be more likely to effect the prostate than the muscle because muscle growth due to steroid ligands is non-genomic, where prostate et al. are transcription based.

    If you really are stressing, I'd stay away from DIM. But again, this is prostate, not muscle.

    Plant-derived 3,3′-Diindolylmethane Is a Strong Androgen Antagonist in Human Prostate Cancer Cells*
    Hien T. Le‡, Charlene M. Schaldach§, Gary L. Firestone¶ and Leonard F. Bjeldanes‡∥
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    Yay an anabolic biochemist's "AMA."

    I got my college degree in Biophysical Chemistry, but none of my lectures focused expressly on the androgenic systems. We have however touched on the subject in my pharmacy school. It's cool you've granted your accumulated knowledge to the masses.

    Anyway, a few questions/points. Answer what you'd like:

    1. Have you come across any incidence of single nucelotide polymorphisms significantly affecting the AR functionality in your lit reviews? If so have these SNP's revealed any unknown or crucial aspects of the AR binding domains that are essential for function? Do some people have AR's that are more easily activated for example? Do you know of disease states where individuals have a non-functional AR and suffer chronic issues?

    2. Are my thoughts on the following subject correct: With regards to the SARMs, the name suggests they are the androgenic parallel to the SERMs, but it seems like this isn't the case based on your previous posts. The SARMs do not selectively bind to different isoforms of the AR since there is only one isoform as opposed to the SERMs which have different affinities for the different estrogen receptor isoforms. Is this more or less accurate? I'm especially curious about the SARMs since my med chem prof Dr. Miller is on the team that developed Ostarine.

    3. I saw someone's post about antiandrogens. Aren't compounds such as cypoterone, bicalutamide, and flutamide viable and available antiandrogens? These are definitely not OTC, but people here have ways of getting what they need. Not that I'd ever use one.

    4. In general terms, how can different steroids produce a distinct anabolic/androgenic (muscle hypertrophy vs sex characteristic proliferation) ratio if there is only one AR isoform? Does it have to do with how easily this compounds can migrate in the body to muscle cells vs other tissues or is it something else altogether?

    If there's anything you'd like me to clarify, let me know.
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    It appears your thread over in Anabolics is your active one. I'll carry my last post over there.
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    I just looked in the anabolic section for this thread and didn't see it. Can someone link me, I'd like to sub to it.

    Br
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    Quote Originally Posted by ZiR RED View Post
    I just looked in the anabolic section for this thread and didn't see it. Can someone link me, I'd like to sub to it.

    Br
    Ask a biochemist anything! Part Deux: The Androgen Receptor
    "The only good is knowledge and the only evil is ignorance." - Socrates
  

  
 

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