1 Number > Size Macromolecules (10 4 to10 6 ) Small molecules (10 2 to10 4 ) Structure Proteins (ribozymes) Most are heterocyclic organic compounds Building Blocks Amino acids (nucleic acids) Vitamins, modified amino acids, nucleotides, metals Active Center Amino acid side chains, metal cofactors Special chemical groups Recycling Always restored to original form during a single cycle Chemically changed by enzyme action; Prosthetic groups EnzymesCoenzymes

2 Acetyl CoA CH 3 C-SCoA O  CoASH  Coenzyme A  CoA H-SCoA CH 3 C-X + O Able to recognize

3 Acetyl CoA CH 3 C~SCoA O 1.An important molecule in metabolism 2.Its main use is to convey the C atoms within the acetyl group to the TCA cycle to be oxidized for energy production. 3.In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). 4.Acteyl-CoA is produced during the second step of aerobic cellular respiration, pyruvate decarboxylation, which occurs in the matrix of the mitochondria. Pyruvate dehydrogenase Pyruvate +NAD + + CoA Acetyl-CoA +CO2 +NADH NAD+ is a common oxidant 5. C~S is a high energy bond energetically favorable for group transfer. 6. It has to couple ATP hydrolysis to regenerate.

4 NADH Nicotinamide Adenine Dinucleotide Coenzymes (NAD; NADP NADH;NADPH) Able to recognize

5 NAD / NADP 1.NAD is a dinucleotide, consists of two nucleotides joined through their phosphate groups. 2.In metabolism, NAD + is involved in redox reactions, carrying electrons from one reaction to another. 3.NAD + is an oxidizing agent – it accepts electrons from other molecules and becomes reduced, to form NADH. 4.NADH is a reducing agent – it can donate electrons. 5.Electron transfer reactions are the main function of NAD +. 6.NADPH is NADH with an extra phosphate group on the 2’ site of the ribose ring that carries the adenine moiety. 7.NADPH usually provides the reducing power for biosynthetic reactions.

6 FAD and FMN Able to recognize

7 FAD / FMN 1.FAD is a redox cofactor involved in several important reactions in metabolism.redoxcofactor 2.FAD can exist in two different redox states and its biochemical role usually involves changing between these two states. FAD can be reduced to the FADH 2, whereby it accepts two H atoms. 3.FMN functions as prosthetic group of various oxidoreductases such as NADH dehydrogenase.prosthetic group oxidoreductases NADH dehydrogenase 4.During catalytic cycle, the reversible interconversion of oxidized (FMN), semiquinone (FMNH ) and reduced (FMNH 2 ) forms occurs. 5.FMN is a stronger oxidizing agent than NAD+ and is particularly useful because it can take part in both one and two electron transfers.

8 Metabolism

9 Glycolysis

10 Glycosis

11 GAP dehydrogenase Aldehyde Strong oxidant carboxylic acid

12 1,3-BPG is an energy –rich molecule with a greater phosphoryl-transfer potential than that of ATP. Thus, it can be used to power the ATP synthesis from ADP. This is called substrate-level phosphorylation because the phosphate donor is a Substrate with high phosphoryl-transfer potential. ATP production PEP has high phosphoryl-transfer potential, pyruvate (ketone) is much more stable than enol form.

13 Glycolysis summary Inputs: Glucose 2 NAD+ 2 ATP 4 ADP 2 P i Outputs: 2 pyruvate 2 NADH 2 ADP 4 ATP 2 ATP (net gain) Glucose + 2P i + 2ADP + 2NAD + 2pyruvate + 2ATP + 2NADH +2H + + 2H 2 O

14 NAD regeneration

15 +O 2 -O 2 NAD regeneration

16 Transition reaction inputs and outputs from glucose Inputs: 2 pyruvate 2 CoA 2 NAD + Outputs: 2 acetyl CoA 2 CO 2 2 NADH Pyruvate + NAD + + CoA Acetyl-CoA + CO 2 + NADH Pyruvate dehydrogenase Link between glycolysis and TCA cycle

17 TCA Cycle S-CoA

18 Critical steps Citrate synthase isocitrate dehydrogenase 2 nd oxidative decarboxylation Oxidation decarboxylation a-ketoglutarate dehydrogenase Enery-rich thioester compound

19 Critical steps Succinyl CoA synthetase OxidationHydrationOxidation Oxaloacetate is regenerated for next cycle Energy is extracted in the form of FADH2 and NADH

20 Citric acid cycle inputs and outputs per glucose molecule Inputs: 2 acetyl groups 6 NAD + 2 FAD 2 GDP + 2 P Outputs: 4 CO 2 6 NADH 2 FADH 2 2 GTP Extremely efficient: conserve 90% of energy available from oxidation of acetyl CoA Acetyl-CoA + 3NAD + + FAD + GDP + Pi + 2H 2 O 2CO 2 + 3NADH + FADH 2 + GTP + 2H + + CoA

Minimal T CA Glucose Pyruvate Fatty acids Ketone bodies Amino Acids Acetate NADH + H + CO 2 NADH + H + CO 2 GDP GTP FADH 2 NADH + H + 6C4C 4C (2C) CoASH CH 3 C-SCoA O 1 GTP 1 GTP 3 NADH 3 NADH +1 FADH 2 10 ATP/cycle And releases two CO 2 NOTE: 1 NADH  2.5 ATP; 1 FADH2  1.5 ATP; 1 GTP  1 ATP so get = 10 ATP/cycle Will be revisited later in detail!

22 Metabolism  Harvesting electrons for the Electron transport chain

23 Acetyl CoA TCA Connections Amino Acid Synthesis Citrate Oxaloacetate Succinyl CoA  -ketoglutarate Malate Gluconeogenesis Heme Fatty Acid Synthesis Amino Acid and Neurotransmitter Synthesis