METABOLIC ENERGY

Food molecules provide energy because they are reduced compounds, sources of electrons that are released by oxidative biochemical reactions. Enzymes that catalyze biochemical oxidations use small-molecule electron acceptors (electron carriers) as cofactors that capture electrons and donate them to various biochemical reductive reactions. One such cofactor, nicotinamide adenine dinucleotide (NAD⁺) accepts electrons and donates them predominantly for the production of ATP energy. A related cofactor, nicotinamide adenine dinucleotide phosphate (NADP⁺) accepts electrons and donates them predominantly for reductive biosynthetic reactions in which the reaction products are more reduced than the substrates, or to maintain a reducing environment inside cells. NADP⁺ does not donate electrons for the production of ATP energy.

Oxidations that do not occur as part of the electron transport chain (in mitochondria) are referred to as "substrate-level" oxidations. Likewise, the production of ATP by processes that do not involve the participation of the electron transport chain are referred to as "substrate-level" phosphorylations.

Food molecules, in addition to serving as a source of electrons, also provide carbon skeletons for the synthesis of other biological molecules.

SMALL MOLECULE CO-FACTORS REQUIRED FOR METABOLISM

All living organisms require a continual input of energy to maintain the multitude of metabolic reactions in a state far from equilibrium (equilibrium = death).

Three major purposes for energy in biological organisms:

• Mechanical Work - e.g., muscle contraction
• Active Transport - to maintain chemical balance, e.g., cells need to continually pump out Na⁺ ions which are taken in as part of transport mechanisms for other molecules - achieved by the Na⁺/K⁺ ATPase, which uses energy to pump Na⁺ against a concentration gradient. Active transport accounts for about 10% - 30% of the energy needs of an organism.
• Synthesis of essential biological molecules (e.g., protein synthesis).

Adenosine Triphosphate [ATP] is the universal currency of energy in biological processes within cells. It is the link between energy-producing and energy-utilizing systems. Its hydrolysis yields useful energy.

Structural basis for the phosphoryl transfer potential of ATP

• electrostatic repulsion between proximal negative charges
• ADP and P_i have a larger number of resonance forms than ATP

The energy liberated in the hydrolysis of ATP can be harnessed to drive reactions that require an energy input.

• Reactions that wouldn't proceed spontaneously, because they required an input of energy, can proceed if they are coupled to ATP hydrolysis.
• ATP hydrolysis shifts the equilibria of coupled reactions. The equilibrium of a reaction is changed by 10⁸ per ATP molecule hydrolyzed. Thus, if 3 molecules of ATP are hydrolysed in a coupled reaction, the equilibrium of the reaction would be changed by 10²⁴.

ATP is formed from ADP and P_i when fuel molecules are oxidized by chemotrophs (or when light is trapped by phototrophs)
This ATP-ADP cycle is the fundamental mode of energy exchange in biological systems.

• ATP turnover is high. The half-life of an ATP molecule in many tissues is approximately one minute.
• A resting human uses approximately 40 kg of ATP in 24 hours = approximately 1000 tons in a lifetime.
• During strenuous exertion (e.g., sprinting) ATP use can be a high as 0.5 kg / min.

NADH and FADH₂ are the major electron carriers in the oxidation (dehydrogenation) of fuel molecules.

In aerobic organisms the ultimate electron acceptor is O₂. However, electrons are not transferred directly from fuel molecules and their breakdown products to O₂. They are first transferred to the electron carriers (substrate-level oxidations). The reduced forms of these carriers then transfer their high-potential electrons to O₂ by means of an electron transport chain located in the inner membrane of the mitochondria.

• Nicotinamide adenine dinucleotide [NAD⁺] structure; in NAD⁺, R = H, in NADP⁺ R = PO₃^2-
• In the oxidation (dehydrogenation) of a substrate, the nicotinamide ring of NAD⁺ accepts a hydrogen ion and two electrons - the equivalent of a hydride ion.
• The reduced form of this electron carrier is called NADH. In the oxidized form, the pyridine ring nitrogen is tetravalent and carries a positive charge. In the reduced form, NADH, the nitrogen atom is trivalent.
• Reaction type that uses NAD⁺ (typically, but not exclusively, oxidation of an alcohol to a carbonyl).
• Flavin adenine dinucleotide [FAD]
  • The reactive part of FAD is its isoalloxazine ring. It accepts two electrons, and two protons.
  • Reaction type that uses FAD (generally, but not exclusively, a dehydrogenation of a saturated compound with the formation of a double bond)
  • NADPH is the major electron donor in reductive biosynthesis.
    • In most biosynthetic reactions the precursors are more oxidized than the products so reducing power is required. e.g., in fatty acid biosynthesis a keto group is sequentially reduced via an alcohol and an unsaturated aliphatic chain.
    • NADPH differs from NADH in that the 2'-OH of its adenosine moiety is esterified with phosphate. This extra phosphate is a tag that directs this reducing agent to discerning biosynthetic enzymes.
    • NADPH carries electrons in the same way as NADH.
    • NADPH is used almost exclusively for reductive biosynthesis, whereas NADH is used primarily for the generation of ATP.
      Why have both NADP⁺ and NAD⁺ ?
      • The cellular ratio of NADP⁺/NADPH = 0.014
      • The cellular ratio of NAD⁺/NADH = 700
      • The cell can thus maintain a high level of reducing equivalents for biosynthetic reactions while simultaneously maintaining high capacity for substrate-level oxidations so that energy can be generated.

Coenzyme A is a universal carrier and donor of acyl groups (originally "A" stood for acetyl because Coenzyme A was discovered as acetyl Coenzyme A, but it was subsequently recognized that many different acyl groups were attached to the Coenzyme).

• The terminal sulfhydryl group is the reactive site, which forms thioesters with acyl (not only acetyl) groups.
• Acetyl CoA is a common intermediate in different catabolic pathways (e.g., glycolysis, beta-oxidation of fatty acids and amino acid degradation all supply the cellular pool of acetyl CoA).