water insoluble biological molecules

-chemically diverse

-two main classes

1. storage lipids

-triglycerols

2. Structural Lipids

-key component in membrane

-glycolipids, phospholipids

-amphipathic

(nonpolar and polar)

-monocarboxylic acids with aliphatic tails

(carboxyl on 1 end and lots of CH's)

-"heads" - polar carboxyl group

-"tails" - alkane chains

properties vary with chain length and degree of saturation

properties of fatty acids

longer tail = higher melting point (T_M)

-more Van der Waals interactions between adjacent tails

-freedom of rotation around single bonds allows tighter packing of tails

-kinks in chain interfere with Van der Waals interactions

-less energy needed to disorder the array

trans fats are produced in the hydrogenation of unsaturated fats

hydrogenation creates a trans double bond, so these unsaturated fats behave more like saturated ones in membranes and in blood

cofactors

electron carriers

hormones

vitamins

signal molecules PIP2 and PIP3

membrane componenets

diameter of head exceeds volume of tail

forms micelles

-maximizes contact between tails and contact of polar head groups with water

Head and Tails occupy similar diameter of space

form bilayers (favored)

-eliminate the interaction of water and hydrophobic molecules

triacylglycerols (storage fats)

cannot form bilayers because polar heads have small diameter compared with large space occupied by tails

fuel molecules (fat) - stored as droplets in cell 

Phospholipids

-major component of biological membranes

Glycolipids

-sugar-containing lipid

Cholesterol

-a sterol lipid that modulates membrane fluidity

Phospholipids

constructed from four components

-one or more fatty acids

-a platform (usually glycerol) to which fatty acids attach

-a phosphate attached to the last OH

-an alcohol attached to the phosphate

sphingomyelin: a phospholipid in membranes that is not derived from glycerol

-the backbone of sphingomyeling is sphingosine

sugar-containing lipids derived from sphingosine or glycerol

one or more sugar molecules linked to the primary hydroxyl of the sphingosine backbone (ceramide)

one or more sugar molecules attached to C3 of diacylglycerol, sometimes sulfonate

more complex glycolipids have a branched chain of up to 7 sugars

-gangliosides

sphingosine with oligosaccharide head group

function in cell recognition

most abundant steroid lipid in body

important for membrane fluidity

eukaryotes have cholesterol, prokaryotes do not

clean up the environment (endocytosis)

Communicate with the outside world (receptors, self antigens)

Communicate with the neighbors (gap junctions, desmosomes)

anchor cytoskeleton

control entry and exit of cellular materials

Permeability

Availability of Energy Source

gases and steroids pass freely through the membranes because of their hydrophobicity

all other molecules must be helped through the membranes including water

concentration gradient

hydrolysis of high energy molecules

ΔG = RTln Cfinal/Cinitial

movement of substance down concentration gradient is spontaneous

C₂ << C₁ , -ΔG

movement of substance up concentration gradient is endergonic

C₁ is final product, +ΔG

movement of molecules and ions in a thermodynamically downhill direction

facilitated by transmembrane proteins (normally need protein channel that takes outside to inside to go through)

also called facilitated diffusion

-channels through membrane

-carrier proteins (passive transporters)

-movement down concentration gradient - no input of energy

drive transport in a thermodynamically uphill direction

requires an input of energy such as ATP hydrolysis

protein channels through membrane

-allow small non-permeable molecules through membrane

-specialized structures, accessible to limited classes of molecules

not saturable

-they dont have a transport maximum

movement down concentration gradient

-no input of energy

Water accessible carbonyl oxygens lead the way into the channel

hydrophilic side contains His, Arg, Asn - essential for selectivity

channel narrows to 2.8Angstrums in diameter (constriction)

-so only one h2o molecule can get through at at ime

pumps exist in one of two interconvertable conformational states

Energy must be expended to pump ions in a single direction

Energy expenditure coupled to conformational change

2 molecules cross membrane in different directions out of cell

1 molecule with concentration gradient, 1 against

lipid bilayers form spontaneously by self-assembly

driving forces

-hydrophobic interactions

-van der waals interactions (tightly packing of fatty acid tails)

-electrostatic interactions and H bonding

Bilayers close on themselves to form vesicles

Extensive

Self-Sealing

-do not have holes because it is not energenetically favorable

lipids can move rapidly laterally, but transverse diffusion is slow

flipping phospholipids requires a flippase (outside to inside), floppase (inside to outside) or scramblase (bidirectional) enzymes

lipid bilayers form spontaneously by self-assembly

membranes are structurally asymmetric

membranes are functionally asymmetric

bilayers are permeable to some molecules

bilayers are fluid

permeability depends on the degree of hydrophobicity

ions have very low permeability

small, charged or polar move across more readily than ions, but not as well as uncharged/hydrophobic molecules

water is the most permeable of the group

molecules traversing membrane must

-shed solvation shell

-dissolve in hydrocarbon core

-diffuse to the other side of the membrane

-become resolvated by water

Fluidity is controlled by fatty acid composition and cholesterol

depending on temperature, membranes can exist as a gel like solid or a more liquid like state called a liquid crystal some areas are ordered and some are not

the sharpness of the transition between gel and liquid crystal depends on

-fatty acid chain length

-degree of saturation

-cholesterol content (in animals only)

process of translating information from outside of the cell (neurotransmitters, hormones, growth factors) into a specific and limited cellular response

Shape and charge are important fo binding to receptor

HAS TO BE SPECIFIC

-signal molecule fits binding site on its complementary receptor; other signals do not fit

signal - primary messenger

interaction with receptor on cell

second messenger relays info from ligand-receptor complex

activation of effectors causes response

Metabolism is limited by:

Limited types of energy currencies

Limited numbers of intermediates that connect pathways

limited types of reactions

limited types of regulation mechanisms

large molecules broken down to small molecules

degradative reactions

nutrients and cell constituents broken down for energy and raw materials

biosynthetic reaction

production of biological molecules from simpler components

requires an input of energy

many are linear

individual reactions must be specific

-takes 1 or a set of substrates and produces 1 product

pathways must be thermodynamically favorable

-even if an individual reaction is not favorable

Metabolic pathways are irreversible

-exergonic reactions within pathway give the pathway directionality

controlling activity of the enzyme for a non-equilibrium reaction can determine the flux of metabolites

opposing reactions create a cycle

-reactions occur simultaneously

overall direction of a pathway can be determined by relative rates of enzyme activity

rate of enzyme 3 > rate of enzyme 4

- net flux favors formation of D

-goes forward in pathway

rate of enzyme 4> rate of enzyme 3

-net flux favors formation of C

-go backwards or continue in cycle until enough D

-nicotinamide adenine dinucleotide

-reactive site = nicotinamide ring - can accept or donate proton from site

-major electron carrier of catabloic oxidation reduction reactions

-accepts a hydride ion

nicotinamide is derived from niacin

nicotinamide adenine dinucleotide phosphate

reactive site = nicotinamide ring

electron carrier for synthetic anabolic reactions

- flavin adenine dinucleotide

-reactive site = isoalloxazine ring

- also electron carrier for catabolic oxidation reduction reactions

can accept 2 electrons and 2 protons

- derived from riboflavin (vitamin B2)

beta mercaptoethylamine

pantothenic acid

P-ADP

- 2 acyl groups are common intermediates in both catabolic and anabolic reactions

- sulfhydryl group binds carbons with thioester bond

another bond that has a high transfer potential G = - 31.4 kJ/mol

- electron transfer

--usually involves transfer of electrons to a carrier

--makes or removes a double bond

--loss or gain of a H

- catalyzed by oxido-reductase enzymes

forming C-C bonds

using free energy from ATP hydrolysis to make larger molecules from smaller ones

catalyzed by ligase enzymes

-rearranging atoms within a molecule

-usually done to prepare a molecule for a subsequent reaction

-catalyzed by isomerase enzymes

transfer of a functional group to a molecule

includes transfer of phosphoryls, acyls, and adenylates etc.

class of enzymes called transferases (including kinase)

- cleave bonds by addition of water

-extremely common reaction in catabolic processes

-class of enzymes called hydrolases

---proteases catalyze hydrolysis reactions

controlling enzyme concentrations

-change rate of transcription

-change rate of degradation

controlling catalytic activity

-reversible allosteric control

-feedback inhibition

-reversible covalent modification

controlling substrate accessibility

-compartmentalization helps control moveemnt of substrates into cell and subcellular compartments

only source of energy for RBCs

only energy source for brain

Metabolism of Glucose

Aerobic

Metabolism of Glucose

Anaerobic

tissue specific metabolism of glucose

liver

- only organ that can carry out all metabolic functions

-primary function is to maintain stable blood glucose level to "feed" other tissues

-stores glucose in glycogen when there is a high supply and releases as needed

-makes fatty acids to store in adipose

-metabolizes amino acids, makes proteins

tissue specific metabolism of glucose

muscle

-converts chemical energy to mechanical energy

-mostly catabolic tissue - burns glucose and fat for energy

-limited anabolic potential - stores glucose in glycogen, makes tissue specific proteins

tissue specific metabolism of glucose

brain

- glucose dependent organ

- prime O2 consuming organ - uses 20% of entire body's O2

-burns glucose exclusively for ATP to make Na+ - K+ ATPase

-anabolic reactions included tissue specific molecules, neurotransmitters

Tissue Specific Metabolism of Glucose

Adipose

- storage depot

-recieves triglycerides from liver and gut to store as fuel reserve

-supports liver metabolism by supplying glycerol to make into glucose

-supports muscle metabolism by supplying fatty acids to burn for energy

high glucose levels facilitate glucose entry into liver and pancreas

muscle and adipose can only transport in glucose when given insulin signal

anaerobic breakdown of glucose to pyruvate

set of 10 reactions

occurs in cytoplasm

Step 1 - preparatory phase

- energy invested to produce activated sugars

-Fructose 1,6 bisphosphate splits into 3-carbon sugars

- phosphorylation of glucose and its conversion to glyceraldehyde 3-phosphate

Step 2 - Pay off Phase (because gets ATP)

- ATP produced by oxidation of 3-carbon sugars

-end up with 2 pyruvates

-oxidative conversion of glyceraldehyde 3-phosphate to pyruvate and coupled formation of ATP and NADH

Reaction 1

Hexokinase

-trapping enzyme

-phosphorylates glucose and traps it in cell for metabolism

-increases free energy of glucose - investment of energy

-glucose to glucose-6-phosphate

-(ATP TO ADP)

Reaction 2

Phosphohexose isomerase

-aldose to ketose

-makes symmetrical molecule

Glucose-6-phosphate to fructose-6-phosphate

(mg)

Reaction 3

Phosphofructokinase

-major regulating step - once glucose reaches this point it is committed to catabolism

Fructose-6-phosphate to fructose-1,6-bisphosphate

(atp to adp)

(mg)

Reaction 4

Aldolase

-produce 2, interconvertible 3-C sugars

Fructose-1,6-bisphosphate to dihydroxyacetone and glyceraldehyde-3-phosphate

Reaction 5

Triose Phosphate Isomerase

-catalyzes reversible conversion of DHAP to GAP

dihydroxyacetone to glyceraldehyde-3-phosphate

Reaction 6

Glyceraldehyde-3-phosphate dehydrogenase

G3PDH

-oxidation reduction reaction

-saves redox energy as reduced cofactor NADH

-adds inorganic phosphate to make high energy intermediate

Glyceraldehyde-3-phosphate + inorganic phosphate to 1,3-bisphosphoglycerate

(NAD+ to NADH + H+)

Reaction 7

Phosphoglycerate Kinase

-substrate level phosphorylation

-transfer of phosphate from high energy donor to ADP to make ATP without ATP synthase or photosynthesis

1,3-bisphosphoglycerate + ADP to 3-phosphoglycerate + ATP

(mg)

Reaction 8

Phosphoglycerate Mutase

-isomerization

-creation of molecule with high energy potential

3-phosphoglycerate to 2-phosphoglycerate

(Mg)

Reaction 9

Enolase

-dehydration reaction

-add double bond

2-phosphoglycerate to phosphoenolpyruvate

(h2o)

Reaction 10

Pyruvate Kinase

2nd substrate level phosphorylation

Phosphoenolpyruvate to pyruvate

(Mg and K)

1 glucose + 2ADP + 2Pi + 2NAD+ --> 2 Pyruvate + 2ATP + 2NADH + 2H+ + 2H20

in anaerobic conditions NAD+ cannot be regenerated through the oxidation of pyruvate and NADH

in animal tissues - fermentation of pyruvate to lactate

in microorganisms - fermentation of pyruvate to ethanol

Sucrose - disaccharide of fructose and glucose

Lactose - dissacharide of galactose and glucose

Fructose and Galactose must be converted to glucose in order to be metabolized

high energy change

[ATP] > [AMP]

hexokinase

phosphofructokinase - committed step

pyruvate kinase

Hexokinase

(in muscle)

first enzyme in glycolytic pathway

inhibited by glucose-6-phosphate

feedback inhibition

PFK

phosphofructokinase

Tetramer with allosteric binding sites

-ATP binding with allosteric site reduces enzyme activity

-AMP binding with allosteric site increases enzyme activity

PFK activity increases when ATP/AMP ratio decreases

at low ATP

-R state favore, high affinity

-catalytic sites are occupied, but not the allosteric sites

at high ATP

-low affinity

-sigmoidal curve

-allosteric sites are occupied

pyruvate kinase

in muscles

also allosterically inhibited by ATP/AMP ratio

alanine is another allosteric inhibitor

-is a transamination product of pyruvate

Liver works to maintain blood-glucose levels

When glucose is abundant

-stores it as glycogen

-makes it into fatty acids to deliver to adipose

When glucose is scares

-mobilize it from glycogen stores

-makes it denovo

from beginning (scratch)

primary enzyme for formation of glucose-6-phosphate

lower affinity for glucose than hexokinase

is not inhibited by glucose-6-phosphate

-regulated by energy charge as in muscle

-regulated by abundance of anabolic precursors

-fructose-2,6-bisphosphate - most important activator in PFK in liver

fructose 2,6 bisphosphate is synthesized from fructose 6 phosphate

-when fructose 6 phosphate abundant fructose 2,6 bisphosphate increases

Fructose 2,6 bisphosphate binding to PFK increases affinity for fructose 6 phosphate and decreases inhibitory effects of ATP

net effect is to increase glycolysis when glucose is abundant

-last step in glycolysis

-regulated allosterically and by covalent modification

-phosphorylated reduces enzyme activity dephosphorylated increases enzyme activity

-regulation important in control of flux through glycolysis

-making new glucose from lactate, pyruvate, and non-carbohydrate precursors

-NOT  a reversal of glycolysis

to make thermodynamically favorable, must counter exergonic (irreversible)reactions in glycolysis

pyruvate kinase --> pyruvate carboxylase, PEP carboxykinase

phosphofructokinase --> fructose 1,6 bisphosphatase

hexokinase or glucokinase --> glucose-6-phosphatase

first step - (in mitochondria)

-catalyzed by pyruvate carboxylase

second step - (in cytoplasm)

-catalyzed by PEP carboxykinase

Fructose-1,6-Bisphosphate to Fructose-6-phosphate

gluconeogenesis

-irreversible step in gluconeogenesis

-catalyzed by fructose-1,6-bisphosphatase

-releases orthophosphate (Pi)