Amino acid catabolism Pt. 2 & Diabetes Flashcards
The urea cycle makes ammonia into urea so…
excess nitrogen can be excreted
Urea cycle Step 0
Ammonia and CO2 are made into Carbamoyl phosphate
Ammonia and CO2 are made into…..
Arginine, then into urea
Urea Cycle Step 1
Carbamoyl + Ornithine -> Citrulline
Urea cycle step 2
Citrulline + Aspartate -> Argininosuccinate
Urea cycle step 3
Argininosuccinate -> Arginine
Urea cycle step 4
Arginine -> Ornithine + Urea
Glutamine, Glutamate and Alanine “____” amino groups into the urea cycle
Feed
Carbamoyl phosphate synthase I
the first nitrogen enters from ammonia.
The terminal phosphate groups of two molecules of ATP are used to form one molecule of carbamoyl phosphate
(two activation steps)
Urea cycle takes place in…
in mitochondria and cytosol of liver
One amino group enters the urea cycle as ________, formed in the matrix
carbamoyl phosphate
The other amino group enters as _____, formed in the matrix by ________ of ________ by glutamate
aspartate, transsmination, oxaloacetate
Energetic cost of urea synthesis
4 ATP bonds but get 2.5 ATP back so about 1.5 ATP/urea
Nitrogen metabolism
Proline synthesis
Glutamate -> -> -> Proline
- 1 ATP, 2 NADPH used
Aspartate synthesis
Oxaloacetate + Glutamate -> Aspartate + alpha-Ketoglutarate
Asparagine synthesis
(not a transamination reaction)
Aspartate + ATP -> beta-aspartyladenylate –(b)–> Asparagine
b: Glutamine -> Glutamate
Alanine synthesis
Alanine –(a,b)–> Pyruvate -> Glucose or Acetyl CoA
a = Alanine: alpha-ketoglutarate aminotransferase
b = Alpha-ketoglutarate -> Glutamate
Serine synthesis
3-phosphoglycerate + NAD+ –> –> –> Serine
Glycine Synthesis
Serine –(a,b)–> Glycine
a = serine hydroxymethyltransferase
b = tetrahydrofolate -> Methylene-tetrahydrofolate
Tetrahydrofolate
carries a variety of single carbon units
Cysteine synthesis
Serine + Homocysteine –> Cysteine + a-ketobutyrate
Tyrosine synthesis
Phenylalanine –> Tyrosine
Nitrogen excretory product
mammals - urea
birds - uric acid
fish - ammonia
Transaminases
amino groups transferred to Glu and Asp
Glutamate dehydrogenase
amino group of Glu released as ammonium ion
Urea cycle
Ammonium ion, carbon dioxide, and the terminal group of Arg utilized to make urea
Warburg Effect
main product of aerobic glycolysis in cancer cells is lactic acid
Importance of Nucleotides: ATP
energy storage
Importance of Nucleotides: UTP
carbohydrate metabolism
Importance of Nucleotides: CTP
phospholipid metabolism
Importance of Nucleotides: GTP
protein synthesis
Importance of Nucleotides: NAD, NADP, FAD
coenzymes
Importance of Nucleotides: AMP, ADP, ATP, etc.
allosteric regulators
Importance of Nucleotides: cAMP, cGMP
second messengers
Importance of Nucleotides: dATP, dGTP, dCTP, dTTP
DNA synthesis
Importance of Nucleotides: ATP, GTP, CTP, UTP
RNA synthesis
Five nitrogen bases
Adenine, Guanine, Cytosine, Thymine, Uracil
Nucleotide synthesis
- Ribonucleotides synthesized first
- Deoxyribonucleotides formed from ribonucleotides by ribonucleotide reductase using NADPH
-dUMP is methylated to make dTMP
Methotrexate
slows cell growth
Two types of Diabetes
Diabetes Mellitus, Diabetes Insipidus
Diabetes Mellitus
body does not produce enough insulin or does not properly respond to insulin, which results in high glucose levels
Diabetes insipidus
(rare) characterized by excessive thirst and excretion of large amount of dilute urine. Results from malfunction of the vasopressin/antidiuretic hormone system
Both types of diabetes are characterized by….
required urination
Mellitus - sweet urine
Insipidus - unsweetened urine
Oral glucose tolerance test
determines the rate of glucose removal from blood
OGTT levels between 140-200 mg/dL indicate impared tolerance
> 200 confirms diabetes
Uncontrolled diabetes results in ______
very high blood glucose concentrations
Two types of Diabetes Mellitus
Type I and Type II
Type I Diabetes
develops when the body produces little or no insulin
no known way to prevent or cure
Type II Diabetes
Develops when the body becomes resistant to insulin
Type I Diabetes develops when….
the body’s immune system destroys pancreatic beta cells
Type I diabetes accounts for…
5% to 10% of diagnosed cases
Demographic of Type I diabetes
usually strikes children and young adults
Type I diabetes is treated with
injected insulin by syringe or pump
Type II diabetes accounts for
90% of all cases of diabetes
Type II diabetes begins as
insulin resistance
as the need for insulin rises, the pancreas gradually loses ability to produce it
Type II Diabetes Demographic
associated with older age, obesity, family history of diabetes, history of physical inactivity, and race
Reduce change of developing Type II diabetes and improve outcome
Exercise and losing weight
Type II Diabetes Treatment
treated with injected insulin or other drugs
history of diabetes
In 1921 in Ontario, Canada. Frederick Banting and Charles Best, kept a severely diabetic dog alive for 70 days by injecting it with dog pancreas
Insulin stimulates
Lipogenesis
- insulin stimulates glucose uptake, glycolysis, fatty acid synthesis but inhibits lipolysis
- Net result is lipid accumulation
The fasting state
or diabetic state, epinephrine and glucagon are elevated
Lack of insulin secretion or response to insulin leads to
GLUT4 (in adipose and muscle) sequestered in the vesicles in the cytosol
Glucose absorption is significantly reduced
Glycolysis pathway is inhibited
Gluconeogenesis in the liver occurs (diabetes)
even though there is enough glucose available, contributing to high blood glucose level in diabetic patients
Lipoprotein lipase (diabetes)
is inhibited, leading to high concentrations of VLDL and Chylomicrons in blood and hypertriacyglycerolemia
Type I Diabetes (cont.)
No insulin secretion
Triacyglycerides in adipose cells are broken down into fatty acids and supplied to other tissues for energy (Lipolysis)
Excessive production of ketone bodies in liver from fatty acid beta oxidation leads to ketoacidosis
Type II Diabetes (cont.)
Patients make insulin but are “insulin resistant” (receptors on liver or muscle cells become insensitive)
Beta-cells don’t make enough insulin to either inhibit gluconeogenesis in the liver or to stimulate glucose uptake by muscle
Lipolysis in adipose cells stil inhibited by insulin. therefore, insulin-resistant diabetic patients rarely have ketoacidosis
Sulfonylurea drugs like Amaryl and Glucotrol
treat type II diabetes
Targets of sulfonyl drugs
ATP-gated K+ channels
increase insulin release from pancreatic beta celss
Roles of Hormones in Fed State
Hormones: Insulin
Role: Stimulates glucose uptake by tissues in response to high blood glucose.
Effect: Promotes glucose export to the brain, adipose, and muscle tissues.
Metabolism: Excess glucose oxidized to acetyl-CoA for fatty acid synthesis and exported as triacylglycerols in VLDLs.
Lipogenic Liver in Fed State
State: Well-fed state
Metabolism: Glucose, fatty acids, and amino acids enter the liver.
Insulin Response: Released to regulate blood glucose and stimulate glucose uptake.
Liver Actions: Glucose oxidized to acetyl-CoA for lipid synthesis, excess amino acids converted to pyruvate and acetyl-CoA.
Dietary Fat Transport in Fed State
Transport: Dietary fats move as chylomicrons via the lymphatic system.
Destination: From the intestine to muscle and adipose tissues.
Roles of Hormones in Fasting State
Hormones: Glucagon
Prevention: Prevents blood sugar from dropping too low.
Liver Response: Induces breakdown of liver glycogen to release glucose into the bloodstream.
Glucogenic Liver in Fasting State
State: Fasting state
Metabolism: Liver becomes the principal source of glucose for the brain.
Substrates: Amino acids from protein degradation, glycerol from TAG breakdown used for gluconeogenesis.
Fuel Usage: Fatty acids used as the principal fuel, excess acetyl-CoA converted to ketone bodies for export.
Hyperglycemia and Alpha-cell Function
Contribution: Inappropriately increased alpha-cell function contributes to hyperglycemia.
Causes: Loss of tonic restraint by high local insulin concentrations on alpha-cells.
Possible Mechanisms: Beta-cell failure, alpha-cell insulin resistance, and involvement of incretin hormones.
Mechanism of Insulin-Stimulated Glucose Uptake
- Insulin release in response to high blood glucose.
- Insulin binds to receptors on cells, triggering a signal pathway.
- Signal transduction leads to GluT4 translocation to the cell membrane.
- GluT4 facilitates glucose transport into the cell.
Result: Blood glucose levels decrease, and cells use glucose for energy.
Importance of Insulin-Stimulated Glucose Uptake
Significance: Crucial for maintaining blood glucose homeostasis.
Function: Provides cells with needed glucose for energy production.
Mechanism of Insulin Secretion from Beta Cells
- Beta cells release insulin to reduce blood glucose.
- GLUT2 transports glucose into beta cells.
- Glucose is metabolized, leading to ATP production.
- ATP-sensitive potassium channels close, causing cell depolarization.
- Voltage-gated calcium channels open, triggering insulin granule exocytosis.
- Other Nutrients and Hormones: Free fatty acids, amino acids, melatonin, estrogen, leptin, growth hormone, and glucagon-like peptide-1 regulate insulin secretion.
- Beta cells act as a metabolic hub connecting nutrient metabolism and the endocrine system.
Quick Response to Blood Glucose Changes
Purpose: Allows the body to respond swiftly to blood glucose level changes.
Result: Maintains homeostasis in the body.
Acute Diabetes Conditions
Conditions:
Hypoglycemia: Low blood sugar, occurs rapidly with insulin overdose.
Diabetic Ketoacidosis: Causes dehydration, labored breathing, coma, and death; results from insufficient insulin leading to excessive ketone body production.
Hypoglycemia
Cause: Too much insulin injected.
Risk: Can lead to coma and death.
Onset: Occurs very fast, within minutes to hours.
Diabetic Ketoacidosis
Cause: Insufficient insulin leading to excessive ketone body production.
Symptoms: Dehydration, labored breathing, coma, and death.
Onset: Develops more slowly, over many hours to days.
Chronic Diabetes Conditions
Conditions:
Chronic Renal Disease: Affecting 10-20% of diabetics, leading cause of end-stage renal disease.
Nerve Disease (Peripheral Neuropathy): Affects 60-70% of diabetics, causing impaired sensation or pain in hands or feet.
Amputations: Most common reason for non-traumatic amputations, typically toes and feet.
Cardiovascular Disease and Stroke: 2-4 times higher in diabetics, exacerbated by smoking.
High Blood Pressure (Hypertension): Most diabetics have elevated blood pressure.
Blindness (Diabetic Retinopathy): Most common reason for blindness in working age.
Measurement of Blood Glucose
Methods:
Glucometer: Device for determining blood glucose concentrations at the moment, changes rapidly.
Hemoglobin A1c: Glycated form of hemoglobin indicating blood glucose concentrations over weeks or months, changes slowly.
Chronic Renal Disease
Prevalence: Affects 10-20% of diabetics.
Consequence: Leading cause of end-stage renal disease.
Nerve Disease (Peripheral Neuropathy)
Prevalence: Affects 60-70% of diabetics.
Symptoms: Impaired sensation or pain in hands or feet.
Amputations
Prevalence: Most common reason for non-traumatic amputations.
Affected Areas: Usually toes, feet, etc.
Cardiovascular Disease and Stroke
Risk: 2-4 times higher in diabetics.
Exacerbating Factor: Smoking worsens the risk.
High Blood Pressure (Hypertension)
Prevalence: Most diabetics have high blood pressure.
Blindness (Diabetic Retinopathy)
Prevalence: Most common reason for blindness in working age.
Hemoglobin A1c Test
Development: Introduced in 1979.
Significance: Standard measurement for blood sugar control in the Diabetes Control and Complications Clinical Trial (1983-1993).
Outcome: People who controlled blood glucose had fewer complications.
Importance of Hemoglobin A1c Test
Pre-1979: Little emphasis on maintaining strict control over blood glucose levels.
Post-1979: Hemoglobin A1c became a key indicator of blood glucose control.
Hemoglobin Glycation
Process: Elevated blood glucose leads to glycation of proteins.
Measurement: Level is proportional to blood glucose concentrations.
Estimation: Used to estimate blood glucose concentrations over weeks, specifically through hemoglobin A1c levels.
Glycated Hemoglobin Levels
Life of RBC: Reflects glucose concentration over the life of a red blood cell (120 days).
Importance: Last 2 weeks are crucial.
Separation: Glycated hemoglobin is separated from normal hemoglobin based on size and charge.
Expression: Expressed as a percentage of total hemoglobin.
Normal and Extreme A1c (%) Levels
Normal Range: 5%
Extreme Range: 13%
Target: Aim to keep below 7%.
Risk Reduction (A1c Levels)
Correlation: For every 1% reduction in glycosylated A1c.
Outcome: Corresponds to a 10% decrease in the risk of vascular complications.
Why High Glucose is Bad
Reason: Inappropriate glycation of proteins.
Consequence: Glycated proteins have altered activities, solubilities, and degradation properties.
HbA1c Formation during Hyperglycemia
Process: Glucose reacts non-enzymatically with the NH2 group on the amino terminus of hemoglobin.
Result: Forms HbA1c, accounting for more than 12% of total hemoglobin in a diabetic patient.
Effects of Glycation on Proteins
Changes: Glycated proteins exhibit altered activities, solubilities, and degradation properties.
Example: Blurred vision due to diabetic cataracts caused by increased glycation of lens proteins, making the eye lens cloudy.
Diabetic Cataracts
Cause: Increased glycation of lens proteins.
Effect: Cloudiness in the lens of the eye, leading to blurred vision.
Increased Risk for Cardiovascular Disease
Risk Factor: Glycated proteins and lipoproteins.
Recognition: Recognized by macrophages.
Consequence: Can lead to accelerated atherosclerosis.
Outcome: Increased risk for cardiovascular disease.
