FATE OF C SKELETON

· Standard AAs are degraded to one of 7 metabolic intermediates: pyruvate; a-ketoglutarate; succinyl-CoA; fumarate; oxaloacetate; acetyl-CoA; or acetoacetate.

· Fig. 20-13

· In animals, Leucine and Lysine are the only two purely ketogenic AAs (i.e. they can be converted to acetoacetate or acetyl-CoA; no net synthesis of pyruvate or any of the TCA intermediates).

· Five AAs (Isoleucine; Threonine; Phenylalanine; Tyrosine; Tryptophan) are both glucogenic (i.e. they are first converted to pyruvate or any of the TCA intermediates) and ketogenic.

· 13 other AAs are purely glucogenic.

KETOGENESIS

(Chapter 19, section 3, pp. 649-650. Fig. 19-21)

· A mitochondrial process by which acetyl-CoA is converted to acetoacetate and D-β-hydroxybutyrate.

· Ketone Bodies: acetoacetate, D-β-hydroxybutyrate, and acetone.

· Ketone bodies are water-soluble equivalents of fatty acids.

· Important metabolic fuels for peripheral tissues, especially heart and skeletal muscle.

· The brain utilizes glucose for energy under normal circumstances. However, ketone bodies become brain’s major fuel source during starvation.

A. Formation of Acetoacetate in Mitochondria

· Thiolase

· Hydroxymethylglutaryl-CoA synthase b-Hydroxymethylglutaryl-CoA

(Corresponding enzymes also exist in cytosol which, together with HMG-CoA reductase, function in mevalonate synthesis.)

· HMG-CoA Lyase

B. Formation of D-β-Hydroxybutyrate

· β-Hydroxybutyrate Dehydrogenase

Note:

· FAs β-Oxidation:

enoyl-CoA hydratase 3-L-hydroxyacyl-CoA DH

trans-∆²-enoyl-CoA → L-β-hydroxyacyl-CoA → β-ketoacyl-CoA

· FAs synthesis:

β-ketoacyl-ACP reductase β-hydroxyacyl-ACP dehydrase

β-ketoacyl-ACP → D- β-hydroxyacyl-ACP → trans-∆²-enoyl-ACP

C. Formation of Acetone (by a facile nonenzymatic reaction)

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Utilization of Ketone Bodies (Fig. 19-22)

Liver releases acetoacetate and β-hydroxybutyrate → carried by blood stream

→ peripheral tissues → converted to acetyl-CoA and used as fuels.

TETRAHYDROFOLATE AND AA METABOLISM

· Structure of Tetrahydrofolate (p. 704)

· Conversion of Folate D Dihydrofolate D Tetrahydrofolate (Fig. 20-19)

· Oxidation Levels of C1 Groups Carried by THF (Table 20-2)

· Consider “N” the equivalent of “O”

Methanol HO–CH₃ =N–CH₃ N⁵-Methyl-THF

Formaldehyde H₂C=O =N–CH₂–N= N⁵,N¹⁰-Methylene-THF

Formate HC(OH)=O =N–CH=O N⁵-Formyl-THF; N¹⁰-Formyl-THF

=N–CH=NH N⁵-Formiminol-THF

=N⁺=CH–N= N⁵,N¹⁰-Methenyl-THF

Interconversion of the C1 Units Carried by THF (Fig. 20-20)