13 January 2010

Amino Acid Metabolism



Amino Acid Metabolism
by:Hanley N. Abramson
Professor of Pharmaceutical Sciences
Wayne State University

December 2009

Dynamics of Protein And Amino Acid Metabolism
Dietary Proteins Digestion to Amino Acids
Digestion of Proteins
Stomach: Pepsinogen Pepsin (max. act. pH 2)
Small Intestine: Trypsinogen Trypsin
Trypsin cleaves:
Chymotrypsinogen to chymotrypsin
Proelastase to elastase
Procarboxypeptidase to carboxypeptidase
Aminopeptidases (from intestinal epithelia)

Enteropeptidase
Lumen
Amino Acids Oligopeptides
Intestinal Absorption
Oligopeptides
Amino Acids
Peptidases
Blood
Transport
Protein
Incorporation of NH4+ Into Organic Compounds
Carbamoyl
Phosphate
Synthase I
(CPS-I)
Glutamate
dehydrogenase
a-Ketoglutarate
Glutamate
TCA Cycle
mitochondria
Glutamine
Glutamate
Glutamine
Synthase
Mg++
N of glutamine donated to other compounds in synthesis of purines, pyrimidines, and other amino acids
Biosynthesis of Amino Acids: Transaminations
Glutamate a-Ketoglutarate
Oxaloacetate Aspartate
Glutamate-Pyruvate
Aminotransferase
(Alanine Transferase ALT)
Glutamate-Oxaloacetate
Aminotransferase
(Aspartate Transferase AST)

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Protein Digestion and Absorption



Protein Digestion and Absorption

* Dietary proteins, with few exceptions, are not absorbed.
* Dietary proteins, with few exceptions, are not absorbed.
* They must be digested first into amino acids or di- and tri-peptides.
* Dietary proteins, with few exceptions, are not absorbed.
* They must be digested first into amino acids or di- and tri-peptides.
* Through the action of gastric and pancreatic proteases, proteins are digested within the lumen into medium and small peptides (oligopeptides).


Digestion of protein - hydrolysis
Protein digestion begins in stomach
Pepsin - inactive precursor pepsinogen
Active @ pH 2-3, inactive pH>5
Secretion stimulated by acetylcholine or acid
Only protease which can break down collagen
Action terminated by neutralisation by bicarbonate in duodenum.
N.B. **All proteases (stomach & pancreatic) secreted as inactive precursors. Most protein digestion occurs in the duodenum/jejunum

Activation of pancreatic proteases
Trypsinogen
Trypsin
Enterokinase
Trypsinogen
Chymotrypsinogen
Proelastase
Procarboxypeptidase
Trypsin
Chymotrypsin
Elastase
Carboxypeptidase
Active proteases inactivated by trypsin
peptidases
aminopolypeptidase
transporters
amino acids
Di/tri peptides
Cytoplasmic peptidase

Pancreatic enzymes
Essential for digestion
essential for life
Proteases
Inactive form
Activated in gut
Acinar cells
Lipases Amylases
Active enzymes

Pancreatic Enzymes
* The bulk of protein digestion occurs within the intestine due to the action of pancreatic proteases.

Pancreatic Proteases
* The two primary pancreatic proteases are trypsin and chymotrypsin.
* They are synthesized and packaged within secretory vesicles as inactive proenzymes:
trypsinogen chymotrypsin
* The two primary pancreatic proteases are trypsin and chymotrypsin.
* They are synthesized and packaged within secretory vesicles as inactive proenzymes:

trypsinogen chymotrypsin
The secretory vesicles also contain a trypsin inhibitor to serve as a safeguard against trypsinogen converted to trypsin.

Other Pancreatic Proteases
* Procarboxypeptidase  carboxypeptidase
* Proelastase  elastase

Trypsin
* Trypsinogen is converted to trypsin by the enzyme enterokinase (enteropeptidase) secreted by cells lining duodenum.
* Trypsinogen is converted to trypsin by the enzyme enterokinase (enteropeptidase) secreted by cells lining duodenum.
* Trypsin then activates the conversion of other zymogens from their inactive to active forms.
* Trypsinogen is converted to trypsin by the enzyme enterokinase (enteropeptidase) secreted by cells lining duodenum.
* Trypsin then activates the conversion of other zymogens from their inactive to active forms.
* Inhibition of trypsin will slow activation of other proteases.
* Trypsin catalyzes the splitting of peptide bonds on the carboxyl side of lysine and arginine residues.
* It has a pH optimum of 7.6 to 8.0 (alkaline).
* Classified as a serine protease (serine and histidine at the active site.

Trypsin, Chymotrypsin
* Similar chemical compositions
* Chief differences are specificity of action:
trypsin – lysine, arginine
chymotrypsin – tyrosine, phenylalanine, tryptophan, methionine,leucine
(aromatic or large hydrophobic side chains)

Lock and Key Model of Enzyme Activity

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11 January 2010

Male Reproductive Problems



Male Reproductive Problems
By:Fertilization Specialists
Joshua Prince
Preston Moore
Candace Lindler

Infertility
* Infertility is the inability of a couple to become pregnant
* 6.1 million people in the United States are effected

Treatment
Normospermia with functional defects
Asthenospermia and teratozoospermia
Oligospermia
Untreatable subfertility
Reversible toxin effects
Disorders of sexual function
Gonadotropin deficiency
Obstructive azoospermia
Sperm autoimmunity
Treatable conditions
Primary seminiferous tubule failure
Untreatable sterility
FREQUENCY (%)

TYPE OF INFERTILITY
Table 1. Classification Of Male Infertility By Effectiveness Of Medical Intervention To Improve Natural Conception Rate

* Sperm count equals the number of sperm per cm3 or cc
* The average has dropped in the past 20 years
* 85-90% are treated with medication or surgery
* Lifestyle changes

Normal Reproduction
* Ovulation
* Spermatogenesis
* Sperm meets with egg in fallopian tube
* Fertilization
* Implantation

Male Reproductive System
Female Reproduction System
Normal Spermatogenesis
Testes

* Normal Testes
* 10-14 grams
* Body of the testis
o Epididymis
o Spermatic Cord
* Embryonal Carcinoma
o hemorrhage and necrosis
* Spermatogonium (2N)
Differentiation
* Primary Spermatocyte (2N)
Meiosis I
* Secondary Spermatocytes
Meiosis II
* Spermatids
Differentiation
* Spermatozoa

Spermatogenesis
* Seminferous Tubules
90% of the testis
* Thousands of sperm per second although spermatogenesis 8-10 weeks
* Stored for months
* Degraded and deposited into the circulatory system if not ejaculated

Klinefelter Syndrome
* XXY instead of XX or XY
* usually male
* lower levels of testosterone
* improper formation of semineferous tubules

Bilateral Anorchia
* vanishing testes syndrome
* testes originally present but reabsorbed before or after birth

Oligospermia
* having too few sperm
* due to:
fever
excessive alcohol
smoking
varicocele
orchitis

Azoospermia
* total lack of sperm in ejaculate
* due to:
fever
undescended testicle
obstructions of seminal vesicles
testicle infection

Cryptorchidism
* 30% of males born premature
* 3% of males carried to term
* Predisposes the person to risk of torsion
* Androgen receptor
* Bilateral has six times the impact on infertility
* Increase in Temperature
* Testicular atrophy
* Treated at Childhood

Abnormalities

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Male Obesity and Semen Analysis Parameters



Male Obesity and Semen Analysis Parameters
By:Joseph Petty, MD
Samuel Prien, PhD
Amantia Kennedy, MSIV
Sami Jabara, MD

Background: Obesity

* Obesity is a growing problem.
* The Behavioral Risk Factor Surveillance System, in conjunction with the CDC, conducted a national survey and found that in 2000, the prevalence of obesity (BMI >30 kg/m2) was 19.8%, a 61% increase since 1991.
* Obesity affects female and male fertility.
* In a study comparing IVF success rates and female obesity, it was shown that a 0.1 unit increase in waist-hip ratio led to a 30% decrease in probability of conception per cycle 2.
* In couples complaining of infertility, male factor plays a role in up to 40% of cases.

Background: Semen Parameters
* What parameters best predict fertility?
* National Cooperative Reproductive Medicine Network: 765 infertile couples (no conception after 12 months), and 696 fertile couples
* greatest discriminatory power was in the percentage of sperm with normal morphologic features.

Hypothesis
* Since there is an observed correlation between obesity and male factor infertility, our hypothesis is that an increased BMI is associated with higher rate of abnormal semen parameters, especially sperm morphology.

Recent Studies
* Danish study by Jensen et al. enrolled 1,558 young men (mean 19 years old) when they presented for their compulsory physical exam as part of their country’s military drafting system.
* The authors showed decreased sperm counts and concentration (39 million/mL vs. 46million/mL) in those with an elevated BMI (>25kg/m2). They did not, however, observe a difference in morphology.
* Hormonal differences
* Kort et al. looked at semen analysis results in 520 men
* grouped according to their BMI, and measured the average normal-motile-sperm count (NMS = volume x concentration x %motility x %morphology)
* Kort concluded that men with high BMI values (>25) present with few normal-motile sperm cells
* Hammoud et al., showed a increased incidence of oligospermia and increased BMI and also showed decreased levels of progressively motile sperm
* Considered each parameter separately.

Sexual function
* Agricultural study: The association between BMI and infertility was similar for older and younger men, disproving the theory that erectile dysfunction in older men is a significant factor.
* Hammoud et al., though primarily concerned with hormones, looked at erectile dysfunction directly and showed that there was no correlation with increases in BMI
* Nguyen et al., effect of BMI is essentially unchanged regardless of coital frequency, suggesting that decreased libido in overweight men is not a significant factor

Hormonal Profile
* Danish study, observed decreased FHS and inhibin B levels in the obese.
* Pauli et al., observed with increases in BMI a decreased total T, decreased SHBG, increased estrogen and decreased FSH and inhibin B.
* Inhibin B, cited for its usefulness as a novel marker for spermatogenesis and its role in pituitary gonadotropin regulation.
* Pauli: no correlation of BMI or skinfold thickness with semen analysis parameters, though it was observed that men with proven paternity versus those without had lower BMI.

Interventions: Gastric Bypass

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