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)

Amino Acids Oligopeptides
Intestinal Absorption
Amino Acids
Incorporation of NH4+ Into Organic Compounds
Synthase I
TCA Cycle
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
(Alanine Transferase ALT)
(Aspartate Transferase AST)
Blood levels of these aminotransferases, also called transaminases, are important indicators of liver disease
Metabolic Classification of the Amino Acids
* Essential and Non-essential
* Glucogenic and Ketogenic
Non-Essential Amino Acids in Humans
* Not required in diet
* Can be formed from a-keto acids by transamination and subsequent reactions
* Alanine
* Asparagine
* Aspartate
* Glutamate
* Glutamine
* Glycine
* Proline
* Serine
* Cysteine (from Met*)
* Tyrosine (from Phe*)
* Essential amino acids
Essential Amino Acids in Humans
* Required in diet
* Humans incapable of forming requisite carbon skeleton
* Arginine*
* Histidine*
* Isoleucine
* Leucine
* Valine
* Lysine
* Methionine
* Threonine
* Phenylalanine
* Tryptophan

* Essential in children, not in adults

Glucogenic Amino Acids
* Metabolized to a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl CoA
Phosphoenolpyruvate Glucose
* Aspartate
* Asparagine
* Arginine
* Phenylalanine
* Tyrosine
* Isoleucine
* Methionine
* Valine
* Glutamine
* Glutamate
* Proline
* Histidine
* Alanine
* Serine
* Cysteine
* Glycine
* Threonine
* Tryptophan

Ketogenic Amino Acids
* Isoleucine
* Leucine *
* Lysine *
* Threonine
* Tryptophan
* Phenylalanine
* Tyrosine

Amino Acids Formed From a-Ketoglutarate
Transamination or
Urea Formation
Blood Urea Nitrogen
Synthesis of Nitric Oxide
Nitric oxide synthase (NOS)
Nitric Oxide
Conversion of Serine to Glycine
Sulfur-Containing Amino Acids
High blood levels of homocysteine associated with cardiovascular disease
Methionine Metabolism: Methyl Donation
Pneumocystis carinii infectons
Creatine and Creatinine
Normal Utilization of Phenylalanine ....

Amino Acid Metabolism.ppt


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
Active proteases inactivated by trypsin
amino acids
Di/tri peptides
Cytoplasmic peptidase

Pancreatic enzymes
Essential for digestion
essential for life
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

* 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
Visualization of the Lock and Key Model of Enzyme Function

Lock Key Enzyme Catalysis
* The “Active Site” contains:
* A shape that fits a specific substrate(s)
* Side chains that attract (chemically) the substrate
* Side chains that are positioned to speed the reaction

Enzyme Catalysis
* -OH of serine 195 attacks C=O of peptide bond. Histidine 57 donates a proton to the N of the peptide bond leading to cleavage and acylation of the enzyme. Asp-102 is also involved.

Carboxypeptidase COO- terminal peptide bond
* Hydrolysis occurs most readily if the COO- terminal residue has an aromatic or bulky aliphatic side chain.
* Binding of a typical substrate results in a rearrangement of the active site (induce fit). Glutamate-270, Arginine-145, Arginine-127, Tyrosine-248 are important at the active site.

Trypsin Inhibitors
* Trypsin (protease) inhibitors are found naturally in many seeds, particularly legumes such as soy, peas, other beans.
* heat labile, heat stable
* Osborne and Mendel (1917) – soybeans need to be heated to support growth in rats
* Kunitz inhibitor, Bowman-Birk inhibitor
* Both are inactivated during moist heat treatment.
* Protease inhibitors are proteins which bind to the enzyme, rendering them inactive.
* Symptoms include pancreatic hypertrophy due to stimulated secretory activity.

Absorption of peptides and amino acids
Transport at the brush border
1. Active transport by carrier.
2. Mostly dependent on Na+ gradient - co-transport similar to that for glucose
3. Some amino acids (basic, and neutral with hydrophobic side chains) are absorbed by facilitated diffusion
Protein assimilation affected by - Pancreatitis, congenital protease deficiencies, deficiencies of specific transporters

Absorption of Amino Acids
* The transporters bind amino acids only after binding sodium.
* The fully loaded transporter undergoes a conformational change that dumps Na+ and the amino acid into the cytoplasm. The transporter then reorients back to its original form.

Absorption of Amino Acids
* Absorption of amino acids is dependent on the electrochemical gradient of Na+ across the epithelium.
* The basolateral membrane of the enterocyte contains additional transporters which export amino acids from the cell into the blood (not dependent on sodium gradients).

Absorption of Peptides
* There is virtually no absorption of peptides longer than three amino acids but there is abundant absorption of di- and tri-peptides, probably by a single transport molecule.
* The vast bulk of di- and tri-peptides are digested into amino acids by cytoplasmic peptidases.

Absorption of Intact Proteins
* Absorption of intact proteins occurs rarely.
* Very few proteins can get through the gauntlet of soluble (lumen) and membrane-bound proteases intact.
* “Normal” enterocytes do not have the transporters neededt to carry proteins across the plasma membrane and they can’t permeate tight junctions.

Absorption of Intact Proteins
* Shortly after birth, neonates can absorb intact proteins.
Absorption of Intact Proteins
* Shortly after birth, neonates can absorb intact proteins.
* Most of these intact proteins are immunoglobulins which can be absorbed from the very first milk (colostrum) and this imparts early neonatal passive immunity.

Absorption of Intact Proteins
* Shortly after birth, neonates can absorb intact proteins.
* Most of these intact proteins are immunoglobulins which can be absorbed from the very first milk (colostrum) and this imparts early neonatal passive immunity.
* “Closure” is when the small intestine loses the capacity to absorb intact proteins.

Protein Requirements
* Maintenance = nutritional requirements to stay alive (does not require positive BW gain)
* Growth = positive tissue accretion
* Reproduction = tissue specific growth related to reproduction, reproductive function (milk, eggs, reproductive tissue)

How do you express a protein requirement ?
* Protein percent of the diet
* Amino acid percent of the diet
Growth Will Dictate Feed Intake
Intake Will Dictate Actual Requirement
* Protein percent of the diet
* Amino acid percent of the diet
* Amino acid percent of total protein
How do you express a protein requirement ?

* Protein percent of the diet
* Amino acid percent of the diet
* Amino acid percent of total protein
* Digestible protein percent of the diet

Digestible Protein Estimates
Digestible Amino Acid Determination
How do you express a protein requirement ?
* Protein percent of the diet
* Amino acid percent of the diet
* Amino acid percent of total protein
* Digestible protein percent of the diet
* Ideal Protein ratios (relationships among amino acids)
Economics of Protein Nutrition
Caloric cost of protein deposition
Amino Acid Balance
Dietary Protein/Amino Acid Balance
Protein Quality Evaluation
Protein Efficiency Ratio
Comparison of Protein Sources
Commercial Application of PER

Protein Digestion and Absorption.ppt


11 January 2010

Male Reproductive Problems

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

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

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

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

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

* 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

* having too few sperm
* due to:
excessive alcohol

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

* 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

* Testicular torsion
of the spermatic cord cuts off the venous drainage, leading to hemorrhagic infarction
It is the twisting of the spermatic cords
Immediate treatment
* Testicular cancer

* Acute
o Hypogonadism
+ Suppression of gonadotropin secretion
o Fever
+ The elevated temperature can induce declines in sperm production for months
* Chronic
o elevated gonadotropin secretion
+ leading to primary testicular disorder

* testicle inflammation
* due to:
* Fibropapilloma
o papilloma virus
o induces testicular warts
o inhibits spermatogenesis
* Chlamydia and gonorrhea
o cause scar tissue which results in duct blockage and
o inhibits spermatogenesis

* Heroin and other opiates
o suppression of LH secretion
* Cocaine and Marijuana
o temporarily can decrease 50% of sperm count
o compounds bind to sperm receptors affecting motility and entry to the secondary oocyte
* Smoking Tobacco
o lowers sperm motility
o reduces sperm life


* Hypoplasia via testicular degeneration
* Nutritional factors, systemic infections, toxins, and other environmental factors
* Basement membrane becomes thickened
* Folds and wrinkles leading to tubular collapse
* Can lead to immune-mediated inflammatory response
* DNA Fragmentation

* Testicular Failure
* Androgen receptors
* Cirrhosis
* Tumors
* Illegal steroid
* Feminine characteristics

* Inflammation would cause pain
* Lack of hair
o Androgen deficiency
* Normal volume equals 15 to 35 ml
* Small is equal to 5 ml or less and would also signal androgen deficiency
* Hard lumps would signal tumors
* Softness would signal reduced spermatogenesis

* Enlarged and twisted varicose veins
* 15-20% of men
* Elevates the temperature
* Obstructs passage of semen
* Obstructs oxygen supply

* Polychlorinated biphenyls
o Teratogens
+ bind to the aryl hydrocarbon receptor
+ mimic estrogen, inhibiting the Leydig cells
* Testosterone
o activates mitogen-activated protein kinase
* Pesticides
+ mimics estrogen
* Free Radicals
* Emotional stress
o inhibits secretion of GnRH

Physical Obstruction to Gamete Movement
* Blocked or absent seminal ducts
* Seminal fluid disorders
* Retrograde ejaculation
* Inability to ejaculate

Blocked or Absent Ducts
* Bilateral congenital absence of the vas deferens
* Obstruction of the epididymis or vas deferens
* Mechanical blockage during hernia repairs
* Blocked seminal vesicles

Seminal Fluid Disorders
* Absent antioxidant factors
* Abundant circulating free radicals

Retrograde Ejaculation
* Reverse ejaculation into the bladder
* Causes:
o Prostate surgery
o Certain medications
o Diabetes
o Spinal cord injuries

Inability to Ejaculate
* Erectile dysfunction
o Diabetes
o Prostate surgery
o Urethra surgery
o Blood pressure medications

Hormonal Obstruction to Gamete Movement
* Endocrine disorders
* Steroids
* Unexplained low levels of needed hormones

Endocrine Disorders
* Pituitary disorder
* Feminization
* Kallmann’s syndrome
* Hypothyroidism
* Other Causes
o Steroid Use
o Unexplained low levels of hormones

Improper Fusion of Sperm and Egg
* Antisperm Antibodies
o Immobilization
o Agglutinating
o Sperm-cervical mucus interaction
o Penetration of the egg
o Sperm fertilization
o Zygote development

Improper Fusion of Pronuclei
* CD9 and CD81 antibodies
* 50% of pregnancies
* occur early in development
chemical miscarriage
molar pregnancy

Chemical Miscarriage
* before pregnancy is know
* dies almost immediately after conception
* causes:

chromosomal abnormalities
uterine abnormalities
hormonal deficiency

Molar Pregnancy
* Complete
egg contributes no DNA
two copies of paternal chromosomes
* Partial
egg does contribute DNA
two copies of paternal chromosomes

Male Reproductive Problems


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.

* 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
* One case series of 6 male patients after bariatric surgery showed secondary azoospermia with complete spermatogenic arrest.
* none of the subjects had a semen analysis before the bariatric surgery, but all had fathered a pregnancy previously
* malabsorption of nutrients
* Hammoud et al., part of Utah Obesity Study
* effect of the gastric bypass surgery on sex steroids and sexual function
* Cohort of 64 severely obese men
* Along with a significant decrease in BMI, they found decreased levels of estradiol, and increases in total and free testosterone along with a reported improvement in quality of sexual function.
* Semen analysis parameters were not considered in this study

Study Design
* Retrospective chart review for all couples and individual patients presenting for an infertility consultation and evaluation at the Texas Tech Physicians Center for Fertility and Reproductive Surgery from September 2005 through January 2008.
* Intake questionnaire: demographic, medical, surgical and fertility history.

* Previous pregnancies fathered: current or previous partner
* Psychiatric disorders included any degree of depression, bipolar disorder or any other psychiatric disorder requiring medical therapy.
* Tobacco and alcohol users: whether they admitted to light, moderate, or heavy use, patient underreporting.
* Chemical exposures: contact with pesticides, herbicides, and heavy metals.
* Sexual dysfunction: mainly erectile dysfunction and decreased libido.
* Genitourinary anomalies: hypospadias, varicocele, genitourinary surgery, testicular torsion or inguinal hernia or trauma
* Other medical problems included mainly diabetes, hypertension, thyroid disease, autoimmune disease, and cancer.
* Patients grouped according to their BMI as normal (20-24 kg/m2, N = 24), overweight (25-30 kg/m2, N = 43), or obese (>30 kg/m2, N = 45), as standardized by the World Health Organization
* Semen analysis parameters: morphology, volume, concentration, percent motility, and presence of absence of agglutination, in accordance with World Health Organization (WHO) guidelines
* SPSS statistical software was used to run analysis of variance (ANOVA) and post-hoc Tukey HSD tests between the groups. A p-value <0.05 was considered statistically significant.

Exclusion Criteria
* questionnaire was missing or if they had an otherwise incomplete chart.
* missing vital statistics (i.e. height and weight),
* 235 total charts reviewed,
o 60 no semen analysis or outside lab.
o 63 patients had either missing vital statistics or a missing questionnaire
o This left a total of 112 patients with valid data to be considered.

* The BMI groups were statistically similar as far as demographic characteristics and confounding variables
* There was no statistically significant difference between the semen parameters of all three BMI groups.
* slight trend towards a decreasing sperm concentration with increases in BMI

* In this study, overweight and obese men did not have an increased rate of teratozoospermia, asthenospermia, or oligospermia.

* Inconsistencies
* Small sample size
* Kort and data interpretation
* Change the normal hormonal milieu, addressed by Jensen study.
* Sertoli cell function, increased aromatase, role of leptin
* Aggerholm study: altered hormones not correlated with semen abnormalities in overweight men (25.1-30.0 kg/m2), slightly decreased sperm concentration in overweight but not in obese

Future Studies
* What affects morphology specifically?
o Hormones
o Result of secondary disease, i.e.. Diabetes
o Genetic mutations
o Weight loss surgery and other interventions
* Overall, there is no doubt that increases in BMI have a detrimental effect on male fertility, but a satisfactory explanation of the mechanism for this phenomenon has yet to be given.

Male Obesity and Semen Analysis Parameters

All links posted here are collected from various websites. No video or powerpoint files are uploaded on this blog. If you are the original author and do not wish to display your content on this blog please Email me anandkumarreddy at gmail dot com I will remove it. The contents of this blog are meant for educational purpose and not for commercial use. If you use any content give due credit to the original author.

This site uses cookies from Google to deliver its services, to personalise ads and to analyse traffic. Information about your use of this site is shared with Google. By using this site, you agree to its use of cookies.

  © Blogger templates Newspaper III by Ourblogtemplates.com 2008

Back to TOP