chemiosmotic mechanism of the mitochondria

ionization of hydrogen

2 H + NAD⁺ ® NADH + H⁺

electron transport chain

flavoprotein, ubiquinone, cytochromes

cytochrome A₃, cytochrome oxidase

aTP synthase

Control of glycolysis and oxidative phosphorylation by ATP and ADP

allosteric inhibition of phosphofructokinase

excess citrate

Anaerobic glycolysis

formation of lactic acid

reconversion of lactic and pyruvic acids to glucose

expenditure:  6 ATP

Phosphogluconate pathway

glucose + 12 NADP⁺ + 6 H₂O ® 6 CO₂ + 12 H + 12 NADPH

5 for 6

Transport of lipids in the blood

lipoproteins

Protein metabolism

nonessential and essential amino acids

ATP

synthesis of cellular components

muscular contraction

membrane active transport

glandular secretion

nerve conduction

Phosphocreatine and ATP

~-bond contains 8.5 kcal at STP, 13 kcal at body conditions

Go to beginning

Links

• Referenced sites


• ¹ The glycolytic pathway



• ² Although the 3D version requires the MDL Chemscape CHIME plug-in, this is a nice presentation of the citric acid cycle and
  structure of the coenzymes of the citric acid cycle



• ³ Oxidative phosphorylation
  Korman and McLick’s Pseudorotation Mechanism for ATP synthesis



• Other sites


• The NHLBI National Cholesterol Education Program 2001 guidelines

Nutrition and Metabolism

Nutrition

nutrient - a substance that promotes normal growth, maintenance, and repair

major nutrients - carbohydrates, lipids, and proteins

other nutrients - vitamins and minerals (and technically speaking, water)

grains, fruits, vegetables, meats and fish, and milk products

Carbohydrates

complex carbohydrates (starches) are found in bread, cereal, flour, pasta, nuts, and potatoes

simple carbohydrates (sugars) are found in soft drinks, candy, fruit, and ice cream

glucose is the molecule ultimately used by body cells to make ATP

neurons and RBCs rely almost entirely upon glucose to supply their energy needs

excess glucose is converted to glycogen or fat and stored

the minimum amount of carbohydrates needed to maintain adequate blood glucose levels is 100 grams per day

starchy foods and milk have nutrients such as vitamins and minerals in addition to complex carbohydrates

refined carbohydrate foods (candy and soft drinks) provide energy sources onlyand are referred to as "empty calories"

Lipids

the most abundant dietary lipids, triglycerides, are found in both animal and plant foods

essential fatty acids - linoleic and linolenic acid, found in most vegetables, must be ingested

dietary fats:

help the body to absorb vitamins

are a major energy fuel of hepatocytes and skeletal muscle

are a component of myelin sheaths and all cell membranes

fatty deposits in adipose tissue provide:

a protective cushion around body organs

an insulating layer beneath the skin

an easy-to-store concentrated source of energy

prostaglandins function in:

smooth muscle contraction

control of blood pressure

inflammation

cholesterol stabilizes membranes and is a precursor of bile salts and steroid hormones

Lipids: Dietary Requirements

higher for infants and children than for adults

the American Heart Association suggests that:

fats should represent less than 30% of one's total caloric intake

saturated fats should be limited to 10% or less of one's total fat intake

daily cholesterol intake should not exceed 200 mg

Proteins

complete proteins that meet all the body's amino acid needs are found in eggs, milk, milk products, meat, and fish

incomplete proteins are found in legumes, nuts, seeds, grains, and vegetables

proteins supply:

essential amino acids, the building blocks for nonessential amino acids

nitrogen for nonprotein nitrogen-containing substances

daily intake should be approximately 0.8g/kg of body weight

Proteins: Synthesis and Hydrolysis

all-or-none rule

all amino acids needed must be present at the same time for protein synthesis to occur

adequacy of caloric intake

protein will be used as fuel if there is insufficient carbohydrate or fat available

nitrogen balance

the rate of protein synthesis equals the rate of breakdown and loss

positive - synthesis exceeds breakdown (normal in children and tissue repair)

negative - breakdown exceeds synthesis (e.g., stress, burns, infection, or injury)

hormonal control

anabolic hormones accelerate protein synthesis

Vitamins

organic compounds needed for growth and good health

they are crucial in helping the body use nutrients and often function as coenzymes

only vitamins D, K, and B are synthesized in the body; all others must be ingested

water-soluble vitamins (B-complex and C) are absorbed in the gastrointestinal tract

b₁₂ additionally requires gastric intrinsic factor to be absorbed

fat-soluble vitamins (A, D, E, and K) bind to ingested lipids and are absorbed with their digestion products

vitamins A, C, and E also act in an antioxidant cascade

Minerals

seven minerals are required in moderate amounts

calcium, phosphorus, potassium, sulfur, sodium, chloride, and magnesium

dozens are required in trace amounts

minerals work with nutrients to ensure proper body functioning

calcium, phosphorus, and magnesium salts harden bone

sodium and chloride help maintain normal osmolarity, water balance, and are essential in nerve and muscle function

uptake and excretion must be balanced to prevent toxic overload

Metabolism

metabolism - all chemical reactions necessary to maintain life

cellular respiration - food fuels are broken down within cells and some of the energy is captured to produce ATP

anabolic reactions - synthesis of larger molecules from smaller ones

catabolic reactions - hydrolysis of complex structures into simpler ones

enzymes shift the high-energy phosphate groups of ATP to other molecules

these phosphorylated molecules are activated to perform cellular functions

Stages of Metabolism

energy-containing nutrients are processed in three major stages

digestion - breakdown of food; nutrients are transported to tissues

anabolism and formation of catabolic intermediates where nutrients are:

built into lipids, proteins, and glycogen

broken down by catabolic pathways to pyruvic acid and acetyl CoA

oxidative breakdown - nutrients are catabolized to carbon dioxide, water, and ATP

Oxidation-Reduction Reaction

oxidation occurs via the gain of oxygen or the loss of hydrogen

whenever one substance is oxidized, another substance is reduced

oxidized substances lose energy

reduced substances gain energy

coenzymes act as hydrogen (or electron) acceptors

two important coenzymes are nicotinamide adenine dinucleotide (NAD⁺)and flavin adenine dinucleotide (FAD)

Mechanisms of ATP Synthesis: Substrate-Level Phosphorylation

high-energy phosphate groups are transferred directly from phosphorylated substrates to ADP

ATP is synthesized via substrate level phosphorylation in glycolysis and the Krebs cycle

Mechanisms of ATP Synthesis: Oxidative Phosphorylation

uses the chemiosmotic process whereby the movement of substances across a membrane is coupled to chemical reactions

is carried out by the electron transport proteins in the cristae of the mitochondria

nutrient energy is used to pump hydrogen ions into the intermembrane space

a steep diffusion gradient across the membrane results

when hydrogen ions flow back across the membrane through ATP synthase, energy is captured and attaches phosphate groups to ADP (to make ATP)

Carbohydrate Metabolism

since all carbohydrates are transformed into glucose, it is essentially glucose metabolism

oxidation of glucose is shown by the overall reaction:

c₆H₁₂O₆ + 6O₂ à 6H₂O + 6CO₂ + 36ATP + heat

occurs in three pathways

glycolysis

krebs cycle

the electron transport chain and oxidative phosphorylation

Glycolysis

a three-phase pathway in which:

glucose is oxidized into pyruvic acid

NAD⁺is reduced to NADH + H⁺

ATP is synthesized by substrate-level phosphorylation

pyruvic acid:

moves on to the Krebs cycle in an aerobic pathway

is reduced to lactic acid in an anaerobic environment

Glycolysis: Phase 1 and 2

sugar activation

two ATP molecules activate glucose into
fructose-1,6-diphosphate

sugar cleavage 

fructose-1,6-diphosphate is cleaved into two 3-carbon isomers

dihydroxyacetone phosphate

glyceraldehyde 3-phosphate

Glycolysis: Phase 3

oxidation and ATP formation

the 3-carbon sugars are oxidized (reducing NAD⁺)

inorganic phosphate groups (P_i) are attached to each oxidized fragment

the terminal phosphates are cleaved and captured by ADP to form four ATP molecules

the final products are: 

two pyruvic acid molecules

two reduced NAD⁺ (NADH + H⁺) molecules

a net gain of two ATP molecules

Krebs Cycle: Preparatory Step

Occurs in mitochondrial matrix and is fueled by pyruvic acid and fatty

pyruvic acid is converted to acetyl CoA in three main steps:

decarboxylation

carbon is removed from pyruvic acid

carbon dioxide is released

oxidation

hydrogen atoms are removed from pyruvic acid

NAD⁺ is reduced to NADH + H⁺

formation of acetyl CoA - the resultant acetic acid is combined with coenzyme A, a sulfur-containing coenzyme, to form acetyl CoA

Krebs Cycle

an eight-step cycle in which acetic acid is decarboxylated and oxidized, generating: 

three molecules of NADH + H⁺

one molecule of FADH₂

two molecules of CO₂

one molecule of ATP

for each molecule of glucose entering glycolysis, two molecules of acetyl CoA enter the Krebs cycle

Electron Transport Chain

food (glucose) is oxidized and the hydrogen:

are transported by coenzymes NADH and FADH₂

enter a chain of proteins bound to metal atoms (cofactors)

combine with molecular oxygen to form water

release energy

the energy released is harnessed to attach inorganic phosphate groups (P_i) to ADP, making ATP by oxidative phosphorylation

Hypothetical Mechanism of Oxidative Phosphorylation

the hydrogens delivered to the chain are split into protons (H⁺) and electrons

the protons are pumped across the inner mitochondrial membrane by:

NADH dehydrogenase (FMN, Fe-S)

cytochrome b-c₁

cytochrome oxidase (a-a₃)

the electrons are shuttled from one acceptor to the next

electrons are delivered to oxygen, forming oxygen ions

oxygen ions attract H⁺ to form water

H⁺pumped to the intermembrane space:

diffuses back to the matrix via ATP synthase

releases energy to make ATP

Electronic Energy Gradient

the transfer of energy from NADH + H⁺ and FADH₂ to oxygen releases large amounts of energy

this energy is released in a stepwise manner through the electron transport chain

the electrochemical proton gradient across the inner membrane:

creates a pH gradient 

generates a voltage gradient

these gradients cause H⁺ to flow back into the matrix via ATP synthase

Summary of ATP Production

Glycogenesis and Glycogenolysis

glycogenesis - formation of glycogen when glucose supplies exceed cellular need for ATP synthesis

glycogenolysis - breakdown of glycogen in response to low blood glucose

Gluconeogenesis

the process of forming sugar from noncarbohydrate molecules

takes place mainly in the liver

protects the body, especially the brain, from the damaging effects of hypoglycemia by ensuring ATP synthesis can continue

Lipid Metabolism

most products of fat metabolism are transported in lymph as chylomicrons

lipids in chylomicrons are hydrolyzed by plasma enzymes and absorbed by cells

only neutral fats are routinely oxidized for energy

catabolism of fats involves two separate pathways

glycerol pathway

fatty acids pathway

glycerol is converted to glyceraldehyde phosphate

glyceraldehyde is ultimately converted into acetyl CoA

acetyl CoA enters the Krebs cycle

fatty acids undergo beta oxidation which produces:

two-carbon acetic acid fragments, which enter the Krebs cycle

reduced coenzymes, which enter the electron transport chain

Lipogenesis and Lipolysis

excess dietary glycerol and fatty acids undergo lipogenesis to form triglycerides

glucose is easily converted into fat since acetyl CoA is:

an intermediate in glucose catabolism

the starting molecule for the synthesis of fatty acids

lipolysis, the breakdown of stored fat, is essentially lipogenesis in reverse

oxaloacetic acid is necessary for the complete oxidation of fat

without it, acetyl CoA is converted into ketones (ketogenesis)

Lipid Metabolism: Synthesis of Structural Materials

phospholipids are important components of myelin and cell membranes

the liver:

synthesizes lipoproteins for transport of cholesterol and fats

makes tissue factor, a clotting factor

synthesizes cholesterol for acetyl CoA

uses cholesterol for forming bile salts

certain endocrine organs use cholesterol for synthesizing steroid hormones

Protein Metabolism

excess dietary protein results in amino acids being:

oxidized for energy

converted into fat for storage

amino acids must be deaminated prior to oxidation for energy

deaminated amino acids are converted into:

pyruvic acid

one of the keto acid intermediates of the Krebs cycle

these events occur as transamination, oxidative deamination, and keto acid modification

Oxidation of Amino Acids

transamination - switching of an amine group from an amino acid to a keto acid (usually a-ketoglutaric acid of the Krebs cycle)

typically, glutamic acid is formed in this process

oxidative deamination - the amine group of glutamic acid is:

released as ammonia

combined with carbon dioxide in the liver

excreted as urea by the kidneys

keto acid modification - keto acids from transamination are altered to produce metabolites that can enter the Krebs cycle

Synthesis of Proteins

amino acids are the most important anabolic nutrients, which form:

all protein structures

the bulk of the body's functional molecules

amounts and types of proteins:

are hormonally controlled

reflect each life cycle stage

a complete set of amino acids is necessary for protein synthesis

all essential amino acids must be provided in the diet

State of the Body

the body exists in a dynamic catabolic-anabolic state

organic molecules (except DNA) are continuously broken down and rebuilt

the body's total supply of nutrients constitutes its nutrient pool

amino acid pool - body's total supply of free amino acids is the source for:

resynthesizing body proteins

forming amino acid derivatives

gluconeogenesis

Interconversion Pathways of Nutrients

carbohydrates are easily and frequently converted into fats

their pools are linked by key intermediates

they differ from the amino acid pool in that:

fats and carbohydrates are oxidized directly to produce energy

excess carbohydrate and fat can be stored

Absorptive and Postabsorptive States

metabolic controls equalize blood concentrations of nutrients between two states

absorptive

the time during and shortly after nutrient intake

postabsorptive

the time when the GI tract is empty

energy sources are supplied by the breakdown of body reserves

Absorptive State

the major metabolic thrust is anabolism and energy storage

amino acids become proteins

glycerol and fatty acids are converted to triglycerides

glucose is stored as glycogen

dietary glucose is the major energy fuel

excess amino acids are deaminated and used for energy or stored as fat in the liver

Principal Pathways of the Absorptive State

in muscle

amino acids become protein

glucose is converted to glycogen

in the liver

amino acids become protein or are deaminated to keto acids

glucose is stored as glycogen or converted to fat

in adipose tissue

glucose and fats are converted and stored as fat

all tissues use glucose to synthesize ATP

Insulin Effects on Metabolism

insulin controls the absorptive state and its secretion is stimulated by:

increased blood glucose

elevated amino acid levels in the blood

gastrin, CCK, and secretin

insulin enhances:

active transport of amino acids into tissue cells

facilitated diffusion of glucose into tissue

Diabetes Mellitus

a consequence of inadequate insulin production or abnormal insulin receptors

glucose becomes unavailable to most body cells

metabolic acidosis, protein wasting, and weight loss results as fats and tissue proteins are used for energy

Postabsorptive State

the major metabolic thrust is catabolism and replacement of fuels in the blood

proteins are broken down to amino acids

triglycerides are turned into glycerol and fatty acids

glycogen becomes glucose

glucose is provided by glycogenolysis and gluconeogenesis

fatty acids and ketones are the major energy fuels

amino acids are converted to glucose in the liver

Principle Pathways in the Postabsorptive State

in muscle:

protein is broken down to amino acids

glycogen is converted to ATP and pyruvic acid (lactic acid in anaerobic states)

in the liver:

amino acids, pyruvic acid, stored glycogen, and fat are converted into glucose

fat is converted into keto acids that are used to make ATP

fatty acids (from adipose tissue) and ketone bodies (from the liver) are used in most tissue to make ATP

glucose from the liver is used by the nervous system to generate ATP

Hormonal and Neural Controls of the Postabsorptive State

decreased plasma glucose concentration and rising amino acid levels stimulate alpha cells of the pancreas to secrete glucagon (the antagonist of insulin)

glucagon stimulates:

glycogenolysis and gluconeogenesis

fat breakdown in adipose tissue

glucose sparing

in response to low plasma glucose, the sympathetic nervous system releases epinephrine, which acts on the liver, skeletal muscle, and adipose tissue to mobilize fat and promote glycogenolysis

Liver Metabolism

hepatocytes carry out over 500 intricate metabolic functions

a brief summary of liver functions

packages fatty acids to be stored and transported

synthesizes plasma proteins

forms nonessential amino acids

converts ammonia from deamination to urea

stores glucose as glycogen, and regulates blood glucose homeostasis

stores vitamins, conserves iron, degrades hormones, and detoxifies substances

Cholesterol

is the structural basis of bile salts, steroid hormones, and vitamin D

makes up part of the hedgehog (Hh) molecule that directs embryonic development

is transported to and from tissues via lipoproteins

lipoproteins are classified as:

hDLs -
high-density lipoproteins have more protein content

lDLs -
low-density lipoproteins have a considerable cholesterol component

vLDLs -
very low density lipoproteins are mostly triglycerides

Lipoproteins

the liver is the main source of VLDLs, which transport triglycerides to peripheral tissues (especially adipose)

lDLs transport cholesterol to the peripheral tissues and regulate cholesterol synthesis

hDLs transport excess cholesterol from peripheral tissues to the liver

also serve the needs of steroid-producing organs (ovaries and adrenal glands)

high levels of HDL are thought to protect against heart attack

high levels of LDL, especially lipoprotein (a), increase the risk of heart attack

Plasma Cholesterol Levels

the liver produces cholesterol:

at a basal level of cholesterol regardless of dietary intake

via a negative feedback loop involving serum cholesterol levels

in response to saturated fatty acids

fatty acids regulate excretion of cholesterol

unsaturated fatty acids enhance excretion

saturated fatty acids inhibit excretion

certain unsaturated fatty acids (omega-3 fatty acids, found in cold-water fish) lower the proportions of saturated fats and cholesterol

Non-Dietary Factors Effecting Cholesterol

stress, cigarette smoking, and coffee drinking increase LDL levels

aerobic exercise increases HDL levels

body shape is correlated with cholesterol levels

fat carried on the upper body is correlated with high cholesterol levels

fat carried on the hips and thighs is correlated with lower levels

Body Energy Balance

bond energy released from catabolized food must equal the total energy output

energy intake - equal to the energy liberated during the oxidation of food

energy output includes the energy:

immediately lost as heat (about 60% of the total)

used to do work (driven by ATP)

stored in the form of fat and glycogen

nearly all energy derived from food is eventually converted to heat

cells cannot use this energy to do work, but the heat:

warms the tissues and blood

helps maintain the homeostatic body temperature

allows metabolic reactions to occur efficiently

Regulation of Food Intake

when energy intake and energy outflow are balanced, body weight remains stable

the hypothalamus releases peptides that influence feeding behavior

orexins are powerful appetite enhancers

neuropeptide Y causes a craving for carbohydrates

galanin produces a craving for fats

gLP-1 and serotonin make us feel full and satisfied

Feeding Behaviors

feeding behavior and hunger depends on one or more of five factors

neural signals from the digestive tract

bloodborne signals related to the body energy stores

hormones, body temperature, and psychological factors

Nutrient Signals Related to Energy Stores

high plasma levels of nutrients that signal depressed eating

plasma glucose levels

amino acids in the plasma

fatty acids and leptin

Hormones, Temperature, and Psychological Factors

glucagon and epinephrine stimulate hunger

insulin and cholecystokinin depress hunger

increased body temperature may inhibit eating behavior

psychological factors that have little to do with caloric balance can also influence eating behaviors

Control of Feeding Behavior and Satiety

leptin, secreted by fat tissue, appears to be the overall satiety signal

acts on the ventromedial hypothalamus

controls appetite and energy output

suppresses the secretion of neuropeptide Y, a potent appetite stimulant

blood levels of insulin and glucocorticoids play a role in regulating leptin release

Metabolic Rate

rate of energy output (expressed per hour) equal to the total heat produced by:

all the chemical reactions in the body

the mechanical work of the body

measured directly with a calorimeter or indirectly with a respirometer

basal metabolic rate (BMR)

reflects the energy the body needs to perform its most essential activities

total metabolic rate (TMR)

Total rate of kilocalorie consumption to fuel all ongoing activities

Factors that Influence BMR

surface area, age, gender, stress, and hormones

as the ratio of surface area to volume increases, BMR increases

males have a disproportionately high BMR

stress increases BMR

thyroxine increases oxygen consumption, cellular respiration, and BMR

Regulation of Body Temperature

body temperature - balance between heat production and heat loss

at rest, the liver, heart, brain, and endocrine organs account for most heat production

during vigorous exercise, heat production from skeletal muscles can increase 30-40 times

normal body temperature is 36.2°C (98.2°F); optimal enzyme activity occurs at this temperature

temperature spikes above this range denature proteins and depress neurons

Core and Shell Temperature

organs in the core (within the skull, thoracic, and abdominal cavities) have the highest temperature

the shell, essentially the skin, has the lowest temperature

blood serves as the major agent of heat transfer between the core and shell

core temperature remains relatively constant, while shell temperature fluctuates substantially
(20°C-40°C)

Mechanisms of Heat Exchange

the body uses four mechanisms of heat exchange

radiation - loss of heat in the form of infrared rays

conduction - transfer of heat by direct contact

convection - transfer of heat to the surrounding air

evaporation - heat loss due to the evaporation of water from the lungs, mouth mucosa, and skin (insensible heat loss)

evaporative heat loss becomes sensible when body temperature rises and sweating produces increased water for vaporization

Role of the Hypothalamus

the main thermoregulation center is the preoptic region of the hypothalamus

the heat-loss and heat-promoting centers comprise the thermoregulatory centers

the hypothalamus:

receives input from thermoreceptors in the skin and core

responds by initiating appropriate heat-loss and heat-promoting activities

Heat-Promoting Mechanisms

low external temperature or low temperature of circulating blood activates heat-promoting centers of the hypothalamus to cause:

vasoconstriction of cutaneous blood vessels

increased metabolic rate

shivering

enhanced thyroxine release

Heat-Loss Mechanisms

when the core temperature rises, the heat-loss center is activated to cause:

vasodilation of cutaneous blood vessels

enhanced sweating

voluntary measures commonly taken to reduce body heat include:

reducing activity and seeking a cooler environment

wearing light-colored and loose-fitting clothing

Mechanisms of Body Temperature Regulation

Hyperthermia

normal heat loss processes become ineffective and elevated body temperatures depress the hypothalamus

this sets up a positive-feedback mechanism, sharply increasing body temperature and metabolic rate

this condition, called heat stroke, can be fatal if not corrected

Heat Exhaustion

heat-associated collapse after vigorous exercise, evidenced by elevated body temperature, mental confusion, and fainting

due to dehydration and low blood pressure

heat-loss mechanisms are fully functional

can progress to heat stroke if the body is not cooled and rehydrated

Fever

controlled hyperthermia, often a result of infection, cancer, allergic reactions, or central nervous system injuries

white blood cells, injured tissue cells, and macrophages release pyrogens that act on the hypothalamus, causing the release of prostaglandins

prostaglandins reset the hypothalamic thermostat

the higher set point is maintained until the natural body defenses reverse the disease process

Developmental Aspects

good nutrition is essential in utero as well as throughout life

lack of proteins needed for fetal growth and in the first three years of life can lead to mental deficits and learning disorders

with the exception of insulin-dependent diabetes mellitus, children free of genetic disorders rarely exhibit metabolic problems

in later years, non-insulin-dependent diabetes mellitus becomes a major problem

many agents prescribed for age-related medical problems influence nutrition

diuretics can cause hypokalemia by promoting potassium loss

antibiotics can interfere with food absorption

mineral oil interferes with absorption of fat-soluble vitamins

excessive alcohol consumption leads to malabsorption problems, certain vitamin and mineral deficiencies, deranged metabolism, and damage to the liver and pancreas

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