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Home , Aldose, Anabolism, Ketose, Pentose, Phosphoglucomutase, Ribose

BI/CH 422/622 OUTLINE: Overview of in Animals Key experiments: precursors Light causes , which is from splitting (Hill) NADPH made (Ochoa) Separate from carbohydrate biosynthesis (Rubin & Kamen) Light Reactions reversible steps in a photon irreversible steps – four pigments energetics HOW 2-steps to PEP Light absorbing complexes mitochondria Reaction center Pyr carboxylase-biotin Photosystems (PS) PEPCK PSI – oxygen from water splitting FBPase PSII – NADPH G6Pase Proton Motive Force – ATP Overview of light reactions Synthesis Assimilation – UDP-Glc Stage One – Rubisco Carboxylase Oxygenase Branching Glycolate cycle Stage Two – making - Pathway Stage Three - remaking Ru 1,5P2 Oxidative phase Overview and regulation Calvin cycle connections to biosyn. Non-oxidative/recycling phase C4 versus C3 plants ROS and NADH/NADPH shuttles Kornberg cycle - glyoxylate Regulation of Carbohydrate Anaplerotic reactions

Glycogen Synthesis

Storing a ready-reserve of carbohydrate

1 Glycogen Synthesis Glycogen is Synthesized by Glycogen Synthase

Glycogenin Starts a New Glycogen Chain

Takes 2 “ATPs” to put Glc into (Glc1P & UDP-Glc), but get 33 ATP of potential energy.

Glycogen Synthesis Glycogen Is Synthesized by Glycogen Synthase

Glycogenin Starts a New Glycogen Chain

Takes 2 “ATPs” to put Glc into polymer (Glc1P & UDP-Glc), but get 33 ATP of potential energy.

2 Glycogen Synthesis General Structure of a Glycogen Particle

29 – 212 x 12-14 = 5–50,000 Glc per glycogen (MW = 106 – 107)

fourth – 12th tier

Synthesis of Branches in Glycogen

Pentose Phosphate Pathway

Providing reduced electrons and

3 Pentose Phosphate Pathway

Pentose Phosphate (oxidative) Pathway, sometimes called the pentose- phosphate shunt, is linked to

(Non-oxidative)

Dr. Kornberg: Lecture 02.13.17 (7:28-8:56) 1.5 min

Pentose Phosphate Pathway

• Included in Anabolism because it provides the NADPH needed for so many biosynthetic reduction reactions, as well as the synthesis of . • But, can also be used for a shunt in the of Glc 6-P. • The main products are NADPH and ribose 5-phosphate (Rib 5-P). • Oxidative Phase oxidizes Glc 6-P to make NADPH • Non-oxidative Phase re-cycles pentoses to if not needed for biosynthesis. Uses of Pentose Phosphate Pathway (PPP): ØNADPH is an electron donor. – reductive biosynthesis of fatty acids and – reductive biosynthesis of amino acids and bases – repair of oxidative damage ØRibose 5-phosphate is a biosynthetic precursor of . – used in DNA and RNA synthesis – or synthesis of some coenzymes

4 Pentose Phosphate Pathway Oxidative Phase Generates NADPH and a Pentose

Allosteric inhibition by product NADPH Mechanism

lactone

Pentose Phosphate Pathway Oxidative Phase Generates NADPH and a Pentose

Allosteric inhibition by product NADPH Mechanism

lactone

5 Pentose Phosphate Pathway

5 Mechanism

Mechanism

Pentose Phosphate Pathway

5 Mechanism

Mechanism

6 Pentose Phosphate Pathway () () (ketose) Phosphohexose (aldose)

2C′s 3C′s Ru 5-P

(ketose)

(ketose) (aldose) (aldose) 2C′s

(ketose) (aldose) Non-oxidative Phase Interconverts Rib 5-P to form Glc 6-P • No ATP is used in the non-oxidative phase. • Complete conversion of ribose-5-phosphate to -6- phosphate requires 6 Rib 5-P (30 ) to make 5 Glc 6-P (30 carbons).

Pentose Phosphate Pathway (aldose) (ketose) (ketose) Phosphohexose542 6 isomerase (aldose) 26 2 2

2C′s 3C′s Ru 5-P

24 2 2 12 (ketose) (ketose) (aldose) (aldose) 2C′s

2 (ketose) (aldose) Non-oxidative Phase Interconverts Rib 5-P to form Glc 6-P • No ATP is used in the non-oxidative phase. • Complete conversion of ribose-5-phosphate to glucose-6- phosphate requires 6 Rib 5-P (30 carbons) to make 5 Glc 6-P (30 carbons).

7 Pentose Phosphate Pathway

(ketose) (aldose) (aldose) (ketose) Mechanism

CH2OH : H+ | E-NH + Ketose ⇌ E–N=C Protonated Schiff 2 base (e– sink) TPP | HOCH | HC–O-H :B | R

This carbanion is protonated in aldolase

In transaldolase, it makes a nucleophilic attack on the of the second- ℗ aldose. TPP

Pentose Phosphate Pathway NADPH Regulates Partitioning into Glycolysis versus Pentose Phosphate Pathway

Dihydroxyacetone- phosphate phosphate phosphate •Used in tissues •Used in tissues requiring needing both Rib more NADPH than Rib 5-P – such as the and adipose 5-P & NADPH – ATP is plentiful

•Used in tissues requiring more Rib 5-P than NADPH – such as the lymphocytes and fast growing tissues/cancer cells

8 Pentose Phosphate Pathway Reactive Oxygen Species (ROS) Glutathione (GSH)

gECG

Pentose Phosphate Pathway

•Ubiquinone is naturally “leaky” and facilitates partial reduction of non-Complex III targets. –Single electron transfers result in free radicals. •One method by which the can correct free-radicals is the production of reduced Glc 6-P Dehydrogenase (G6PD) Deficiency glutathione (GSH), which fuels the glutathione shuttle

Reactive Oxygen Species (ROS) Can Damage Biological Glutathione

9 Pentose Phosphate Pathway

How do we get NADPH from PPP in cytosol into mitochondria?

•Ubiquinone is naturally “leaky” and facilitates partial reduction of non-Complex III targets. –Single electron transfers result in free radicals. •One method by which the cell can correct free-radicals is the production of reduced Glc 6-P Dehydrogenase (G6PD) Deficiency glutathione (GSH), which fuels the glutathione shuttle

Reactive Oxygen Species (ROS) Can Damage Biological Macromolecules Glutathione

Pentose Phosphate Pathway Malate-Aspartate Converting Cytosolic Electron Carriers Shuttle (NADH & NADPH) to the Mitochondria

NADPH antiporter NADP+

•This more complicated shuttle is mostly present in liver, heart, and kidney. •It moves NADH & NADPH equivalents antiporter from cytosol to NADH & NADPH equivalents in the mitochondria.

10 Regulation of

Catabolism vs. Anabolism

Catabolism vs. Anabolism Regulation of Carbohydrate Metabolism controlled Catabolism Anabolism Glycogen versus Glycogen Glycogen Synthase Phosphorylase Glycogen Glycogen Synthesis Synthase UDP-Glc

UDP-glucose Glycolysis pyrophosphorylase versus Glc 1-P Gluconeogenesis Glucose 6- • Regulated phosphatase often correspond to

points in the pathways Phosphofructo- 1,6- kinase-1 bisphosphatase that have the same -1 substrate and product, but a different . • Also where there are junctions.

• Can you name those Pyruvate Kinase – PEPCK – Pyruvate enzymes? Dehydrogenase Acetyl-CoA Complex

11 Regulation of Carbohydrate Metabolism Regulation of Complex

• by energy charge and substrate/product –ADP & pyruvate activates –ATP/NADH & acetyl-CoA inhibit • Regulated by reversible of E1 –phosphorylation: inactive –dephosphorylation: active • PDH kinase and PDH phosphatase are part of mammalian PDH complex. –Kinase is activated by ATP. • high ATP à phosphorylated PDH à less acetyl-CoA • low ATP à kinase is less active and phosphoprotein phosphatase removes phosphate from PDH à more acetyl-CoA

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