Tina Cowan, PhD September 28, 2015
Tina Cowan, PhD September 28, 2015
The Map: Foundation of Metabolic Biochemistry
It’s not as hard as it looks….
Week 1
Week 4 Week 3
Week 2
Week 5 Week 6
Course goals for learners
• Describe major pathways of metabolism
• Apply knowledge of metabolic regulation to evaluations of various physiologic states
• Practice clinical reasoning in application of this knowledge
• Recognize examples of inborn errors of metabolism
• Recognize the role of metabolic disruptions in the expression of common diseases
APPLIED biochemical pathways with focus on medical utility
• What does the pathway do? • What are its inputs and outputs? • What other pathways does it interact with? • What are the tissues where it is active? • Where in the cell is it localized? • What are its key regulated steps? • What are key cofactors used in this pathway? • What goes wrong with this pathway in human disease?
Bioc 200: It takes a village
David Mahoney
Daniel Berenson
Megan Garland
Steven Sloan
Your Bioc 200 TAs
Behind the scenes…. Our map artist
Leslie White Medical Illustrator
And the voice of the videos
Julie Theriot, PhD Department of Biochemistry
Bioc 200: Course Elements
1. Self-study videos 2. Check-for-understanding questions (CFUs) 3. Clinical application sessions 4. Current concepts in metabolism
Small-group literature review sessions Lectures (current topics in biochemistry)
5. USMLE-style quizzes 6. Some optional offerings 7. Final exam
https://canvas.stanford.edu/
Weekly schedule: the week begins on Tuesday!
1. Tuesday-Thursday: Self-study videos
Organized in Canvas 4-6 short videos by topic Suggested supplemental readings given Next step: CFUs
Due Thursday before midnight (i.e., by 11.59 pm) 2-3 questions per video Available directly after each video Tests basic understanding Participation required, but answers not graded
2. Check-for-understanding questions (CFUs)
3. Friday: Clinical application session
Fridays 10.30-11.20 am, LKSC 101/102
Clinical applications of weekly material
Teams of 6 students
Real-time problem solving Introduction of a clinical problem
Group discussions and activities
Follow-up discussions with entire class
Slides posted after each session
Team points! Theme-based snacks!
Why is the liver enlarged? Why is my patient hypoglycemic?
Biochemistry in the medical literature
Alternating Mondays 10.30 am Oct. 5, Oct. 19, Nov. 2
Room assignments and readings posted on Canvas
Read posted case reports
Come prepared to discuss study questions
Participation is required for a passing grade
4a. Monday: Current concepts in biochemistry Small group literature review
What is the diagnosis for this patient? How did the routine laboratory test cause such a severe adverse reaction?
Alternating Mondays at 10.30 am, LKSC 130 – October 12 - Metabolism and Cancer
– October 26 - Diabetes
– November 9 - Leveraging metabolic pathways to treat disease
4b. Monday: Current concepts in biochemistry Lecture
Posted each Friday at noon, due before midnight (i.e., 11.59 pm) Monday 10 multiple choice questions, written in USMLE Step 1 format
3 hour limit, single submission Questions require clinical reasoning, not simple recall Detailed explanations provided after submission Consult notes and textbook, but DO NOT consult the internet or each other Cumulative quiz scores count for 30% of final grade (One optional short-answer question for practice, model answer will be posted)
Designed to be challenging!
5. Friday-Monday: Weekly on-line quiz
Putting it all together…..
Final cumulative exercise Friday, Nov 13, 9.30-11.20 am LKSC 101/102 Excitement! Prizes! Fun!
6. Final exam: Overall integration
• Friday, Nov 21 - Written final exam, 8.30-11.20 am, rooms TBA – Closed-book – Open “map,” annotated with your own notes (front and back)
• New maps will be provided at review
– Short-answer – 70% of final grade
Bioc 200: Other resources (optional)
TA office hours - LKSC 4th floor (by printer) Mondays 12.30-1.30 Tuesdays 12.30-1.30 Wednesdays 9-10 and 6-7
Clinical reasoning sessions Mondays 9.30-10.20, LKSC 101/102
TAs work through sample quiz and exam questions
Pathway help Informal help on video material prior to clinical application session Fridays 9.30-10.20 am, LKSC 101/102
Why you should care about metabolic biochemistry #1
Metabolic diseases are common and increasing in frequency
Obesity - 33% of US adults, 17% of children and adolescents
Type II diabetes - 8 % of US adults (27% of those over 65)
Hypercholesterolemia - 16% of US adults
These common disorders shorten lifespan, decrease quality of life, and complicate treatment of other medical conditions.
* BMI (body mass index): weight (kg)/[height (m)]2
Average male in US: height = 5’ 9½” BMI of 30 => 206 pounds
Average female in US: height = 5’ 4” BMI of 30 => 174 pounds
2000
Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010
(*BMI ≥30, or about 30 lbs. overweight for 5’4” person)
2010
1990
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
Medical Correlates of Obesity
CORRELATIONS ≠ proof of causation Predict that a US population with BMI <25 would reduce: -Coronary heart disease by 25% -Strokes and congestive heart failure by 35% -Type II diabetes by 70%
Why you should care about metabolic biochemistry #2
Metabolism is everywhere!
What is G6PD? Why does its deficiency lead to a low red blood cell count? Coming in week 1!
What is IDH? What is the relationship between energy metabolism and cancer? Stay tuned for Week 2!
How are lipid levels modulated? How do lipid-lowering drugs work? Stay tuned for Week 3!
What are the essential amino acids? How are they metabolized? What does this have to do with energy metabolism? Stay tuned for Week 5!
Why you should care about metabolic biochemistry #2
Inborn errors of metabolism: Lessons learned from rare disorders
A recent case in the lab….
A 21 year-old female with new-onset seizures and a history of worsening arthritis and back pain.
Inborn errors of metabolism:
Individually rare Collectively common Provide insights into normal biochemistry
Why you should care about metabolic biochemistry #3
Laboratory studies form the basis of much of clinical practice
www.stanfordlab.com
Metabolites are critical to the diagnosis of disease!
9-month old female with increasing lethargy and irritability
Simple, fast, non-invasive tests on metabolites in urine and blood are standard, early steps in many cases. Metabolite imbalances can provide clues about chronic conditions as well as acute events. Compare with DNA sequencing: Metabolite levels are directly tied to physiology and dependent on many possibly defective genes. Overcomes our limited knowledge of how genetic polymorphisms impact function
Follow-up patient with carnitine-acylcarnitine translocase (CACT) deficiency, identified in newborn period Two deleterious SLC25A20 mutations found by DNA sequencing Treated for hyperammonemia and acidosis, doing well
Newborn Screening: A Widespread Metabolic Test
http://www.cdph.ca.gov/programs/nbs/
Blood droplets from heel stick 1-2 days of age Uses mass spectrometry (MS/MS) and
other platforms Testing for abnormal levels of
metabolites Screening test can detect:
Amino acid disorders (19) Organic acid disorders (17) Fatty acid oxidation disorders (11) Other metabolic disorders (2) Some endocrine disorders Hemoglobin disorders Cystic fibrosis Severe combined immunodeficiency ds
Early identification allows early intervention Most metabolic disorders can be controlled with diet,
supplementation and drugs Early treatment prevents irreversible damage
Why you should care about metabolic biochemistry #4
Let’s Dissect Your Breakfast
200-300 g carbohydrates 4 kcal/g = 800-1200 kcal 70-100 g protein 4 kcal/g = 280-400 kcal 60-90 g fat 9 kcal/g = 540-810 kcal
Average daily energy requirements: 1600-2400 kcal (= dietary “Calories”)
Why do we eat? 1) Extract molecular components of
biological macromolecules from food and rearrange them into human stuff.
2) Convert energy stored in the chemical bonds of food into a form that we can use for activities (walking, thinking, etc.).
A Molecular Picture of Your Breakfast
Sucrose: the most abundant sugar in maple syrup
Alanine: the second most abundant amino acid in bacon
Palmitate: the most abundant fatty acid in butter
Typical Energy Stores of a Human Adult
Note: the brain requires around 6 g glucose/hour
The journey of the carbohydrates begins..
lactase
lactose (milk)
galactose + glucose
amylose (potato)
amylase
glucose
sucrose (table sugar)
sucrase glucose + fructose
Amylase secreted in saliva Many specific glycosidases in lumen of
small intestine, secreted by enterocytes or delivered by pancreas
Normal flora in gut (Bacteroides) also help break down complex carbs
(not expressed in lactose intolerance)
Normal blood glucose: 4.4 -6.1 mM (1 mM = 18 mg/dL) Blood glucose <3 mM diabetic coma; > 8 mM long-term damage. The brain is always scavenging glucose at its maximum capacity. The liver and pancreas uptake glucose proportionately to its concentration in the blood. The large tissue depots (muscle/adipose) require licensing from insulin. GLUT5 deficiency causes fructose malabsorption (stay tuned for next Monday’s case report…..).
Glucose Enters Cells via GLUT Transporters Type Tissue KM Properties
GLUT1/3 Brain 1 mM Always at Vmax
GLUT2 Liver / β-Cells 15 mM Flux linear with [glucose] GLUT4 Muscle / Fat 5 mM Insulin regulated localization GLUT5 Enterocytes 5-10 mM Fructose transporter
Km ~ concentration of substrate where enzyme rate is half-maximal.
And the journey begins….
See you on Friday