biochemistry 330 · • metabolism and bioenergetics (ii) – enzyme catalysis: • kinetic...

Biochemistry 330 September 6, 2011

•  Introductions •  Course Outline and Expectations •  Adverse Childhood Experiences

• Dynamic reach of biochemistry

•  Intro to Biomolecular Structure

BioChem 330 - Course Outline •  Bio-molecular Structure/Function (I)

–  PROTEINS •  Structure

– Chemistry of amino acid building blocks –  Primary, secondary and tertiary structure –  Protein folding, thermodynamics and kinetics –  Predictions of protein folding, dynamics

•  Function –  Binding ….a tale of two globins (hemoglobin and

immunoglobulin)

BioChem 330 - Course Outline •  Bio-molecular Structure/Function (I cont’d)

–  NUCLEIC ACID •  DNA sequence and structure •  Protein/nucleic acid interactions

–  CARBOHYDRATES •  Sugars - mono and disaccharides •  Polysaccharides •  Glycerides and glycerol

–  FATS AND LIPIDS •  Chemistry and nomenclature for fatty acids •  Saturated and unsaturated fatty acids •  Fluid mosaic model of membrane structure

BioChem 330 - Course Outline •  Metabolism and Bioenergetics (II)

–  ENZYME CATALYSIS: •  kinetic constants kcat, Km •  Catalytic strategies, the serine proteases

–  CATABOLISM (breakdown) •  Carbohydrates

– Glycolysis –  Tricarboxylic Acid Cycle –  Electron Transport – Chemiosmosis and ATPase

•  Fatty acids and amino acids

BioChem 330 - Course Outline •  Metabolism and Bioenergetics (II)

–  ANABOLISM (building up) •  Glucose •  Lipid

•  Cellular Communication/Signal Transduction (III) –  Intracellular and short range interactions

•  Neurotransmitters •  Nitric Oxide

–  Intercellular and long range interactions •  Hormones

–  Small molecule –  Peptides and proteins –  Steroid

BioChem 330 - Course Expectations

•  Overall Evaluation: –  Exams (midterm, final) ~65%

•  Exams will be open book (VVP), open notes and powerpoint printouts, •  Midterm (30%) is Thursday, October 20th in class •  Final (35%) is cumulative during final exam period

–  Discussion Section ~20%

–  Additional work ~15% •  Attendance •  Structural WIKI (presentation?) •  Problem Sets

BioChem 330 - Course Expectations

•  Statement of Intellectual Responsibility –  Exams – no copying, consultation, electronic media –  All work submitted without citation is your individual work –  Work can be used from others with citation.

•  Statement of Respect for Persons – Discussion Sections

•  Statement of Individual Rights

BioChem 330 – ACE initiative

•  Adverse Childhood Experiences & Biochemistry –  One novel aspect of this course is our attempt to link theoretical

concepts from lecture with clinical findings and research discoveries that directly relate to Childhood Stress. The collection of factors known as “Adverse Childhood Experiences” have been found to affect almost all aspects of biology, biochemistry, and cellular physiology.

– Why is this important? – How is this relevant? – What can I expect to learn?

BioChem 330 - Course Expectations

•  Discussion Sections – Dr. Aronson •  In our evening sessions, we will meet to discuss papers that bring

together our abstract concepts from class with applied concepts from the clinical literature. Our leading paper and the first one we will read is a landmark study in 1998 called the ACE study in which the health status of 20,000 patients was correlated with childhood stress. As the semester progresses, we will move from structure to metabolism, illuminating how every aspect of biochemistry can be dysregulated by chronic stress.

•  Doctor Aronson and Professor O'Hara will in general assign a paper a week in advance (whenever possible) and will expect participation in an on-line group discussion prior to the Thursday evening sessions. Evening sessions will pick up threads from the on-line discussions.

BioChem 330 - Course Expectations

•  Discussion Sections – Dr. Aronson •  You will all be asked to post an original comment AND to respond to another

student's comment. Each student's comment should have at least one response before you start a threaded discussion.

•  Guidelines for Response: Pick out some aspect of the paper that you find especially notable. What we will especially appreciate when possible are those comments that relate back to material we are studying in lecture. Your comment should be no more than 100 words and should be posted by 8 AM Tuesday

•  Guidelines for Comment on a Peer's Response: The length of your response is up to you. The purpose is to “listen” to each other and learn from each other through respect, reflection, integration, and critical thinking.

–  Ask a thoughtful question. –  Comment on what particularly interested you: what particularly resonated with you, expanded your understanding,

inspired you, and so on. Be very specific. (The best way to do this is to copy the part of the student’s you are commenting on, and paste it into your text before your own comments. That way we can all see what you are talking about.)

–  Disagree respectfully on something your classmate wrote, and explain why you feel the way you do. Be specific.

BioChem 330 General Info •  Fundamentals of Biochemistry: Life at the Molecular Level

–  Text: 3rd Edition Donald Voet, Judith G. Voet, Charlotte W. Pratt, Wiley University Press January 2008

–  Publisher’s Website: www.wiley.com/college/voet

•  330 CMS: https://www.amherst.edu/academiclife/departments/courses/1112F/CHEM/CHEM-330-1112F

–  Structure: office hours, times and rooms, class roster, –  Function: e-links to papers, clinical studies, handout

replacements, announcements, structural wikis, discussion board (responses and comments)

–  Communication: Check your email and I’ll check mine.

Structure and function of biologically important molecules influence phenomena.

•  structure Function PHENOMENA •  size Metabolism DIGESTION •  shape Regulation IMMUNE RESPONSE •  charges Catalysis SIGNAL TRANSDUCTION •  charge distribution Transport CELL DIVISION •  hydrophobicity Transcription MUSCLE CONTRACTION •  amphillicity Translation INFECTION •  location in cell Tight Binding APOTOSIS •  flexibility PHOTOSYNTHESIS

BLOOD CLOTTING •  a A •  b B PHENOMENON •  c C

Structure and function of biologically important molecules influence phenomena.

Size Scale of Biological Molecules and Organisms

organism

100 m

Our study spans at least ten orders of magnitude in size

Structure and function of biologically important molecules influence phenomena.

Time Scale of Biological Molecules and Organisms

Our study spans at least fifteen orders of magnitude in time

Structure and function of biologically important molecules influence phenomena.

Energy Scale of Biological Molecules and Organisms

Our study spans at least four orders of magnitude in energy

Intro To Protein Structure •  Why start with proteins? •  Historical: 1951 Predictions

Linus Pauling who, with R. B. Corey and H. R. Branson predicted all of the elements of secondary structure (alpha helix and beta sheet) based on simple chemical ideas of VSEPR, resonance, and hydrogen bonding (Nobel 1954).

Intro To Protein Structure •  Why start with proteins? •  Historical: 1957 Solved Crystal

Structures –  The first three-dimensional protein

structures (myoglobin and hemoglobin) were determined by M.F.Perutz and J. C. Kendrew (Mb at 6 A resolution in 1957, Nobel Prize in Chemistry in 1962). The entries are included in the PDB (PDB codes: 1mbn and 2dhb).

–  Dorothy Hodgkin’s early work on peptide insulin (Nobel Prize in 1964).

•  Why start with the structure of proteins? •  There is more protein in a cell than anything besides water. •  e. coli weight percent

–  water 70% –  proteins 15% –  RNA 6% –  DNA 1% –  Other 8%

•  How many different kinds of these molecules are there? •  e.coli humans HIV-1 •  Proteins 3,000 100,000 <10 •  RNA 100+ 100+ 101+ •  DNA 1 1 0

Intro To Protein Structure

Structure/Function •  What role do proteins play in biological phenomena?

–  Structural role of living organisms (keratin protein in skin, hair, silk) –  Mechanical role in muscle (actin, myosin, tropomyosin) –  Catalytic role in enzymes of catabolism and anabolism

(dozens of enzymes in glycolysis, TCA cycle) –  Storage role (ferritin, holds about 5000 Fe atoms) –  Synthetic Role (reading and writing enzymes: polymerases, ribosomes) –  Regulatory Role (calcium regulation by calmodulin, insulin)

–  Intercellular Communication (NOS synthase)

Classic Protein Papers http://www.pnas.org/misc/classics1.shtml

•  1. Pauling, L. & Corey, R. B. Atomic Coordinates and Structure Factors for Two Helical Configurations of Polypeptide Chains. PNAS, 37, 235-240, (1951). |Article|

•  2. Pauling, L. & Corey, R. B. The Structure of Synthetic Polypeptides. PNAS, 37, 241-250, (1951). |Article|

•  3. Pauling, L. & Corey, R. B. The Pleated Sheet, A New Layer Configuration of Polypeptide Chains. PNAS, 37, 251-256, (1951). |Article|

•  4. Pauling, L. & Corey, R. B. The Structure of Feather Rachis Keratin. PNAS, 37, 256-261, (1951). |Article|

•  5. Pauling, L. & Corey, R. B. The Structure of Hair, Muscle, and Related Proteins. PNAS, 37, 261-271, (1951). |Article|

•  6. Pauling, L. & Corey, R. B. The Structure of Fibrous Proteins of the Collagen-Gelatin Group. PNAS, 37, 272-281, (1951). |Article|

•  7. Pauling, L. & Corey, R. B. The Polypeptide-Chain Configuration in Hemoglobin and Other Globular Proteins. PNAS, 37, 282-285, (1951). |Article|