BIOCHEM | TCA Cycle

stage 1

Stage of cell respiration

metabolic fuels are hydrolyzed in the gastrointestinal tract to a diverse set of monomeric building blocks (glucose, amino acids, and fatty acids) and absorbed

stage 2

Stage of cell respiration

-the building blocks are degraded by various pathways in tissues to a common metabolic intermediate, acetyl-CoA

-Most of the energy contained in metabolic fuels is conserved in the chemical bonds (electrons) of acetyl-CoA. A smaller portion is conserver in reducing nicotinamide adenine dinucleotide (NAD) to NADH or flavin adenine dinucleotide (FAD) to FADH2, Reduction indicates the addition of electrons that may be free, part of a hydrogen atom (H), or a hydride ion (H-)

stage 3,

Stage of cell respiration

-the citric acid (Krebs, or tricarboxylic acid [TCA]) cycle oxidizes acetyl-CoA to CO2.

-The energy released in this process is primarily conserved by reducing NAD to NADH or FAD to FADH

final stage

Stage of cell respiration

is oxidative phosphorylation, in which the energy of NADH and FADH2 is released via the electron transport chain (ETC and used by an ATP synthase to produce ATP. This process requires O2.

tricarboxylic acid cycle (TCA cycle)

accounts for more than two-thirds of the adenosine triphosphate (ATP) generated from fuel oxidation.

TCA cycle

the __________ is central to energy generation from cellular respiration.

anoxia

Absence of O2

hypoxia

partial deficiency of O2

mitochondria

-Matrix (DNA, ribosome)

-Inner Membrane

TCA cycle happens in

Acetyl Coenzyme A (Acetyl-CoA)

serves as a common point of convergence for the major pathways of fuel oxidation. It is generated directly from the b-oxidation of fatty acids and degradation of the ketone bodies b - hydroxybutyrate and acetoacetate

leucine ; isoleucine

Several amino acids such as _______ and ________ are also oxidized to acetyl-CoA.

pyruvate

Glucose and other carbohydrates enter glycolysis, a pathway common to all cells, and are oxidized to _________

pyruvate

The amino acids alanine and serine are also converted to_______

-Fatty acids (serine & alanine)

-Ketone body

-Sugar

-Pyruvate

-Ethanol

Sources of Acetyl-CoA

Pyruvate

Substrate for the TCA cycle, generated in the cytoplasm.

Pyruvate translocase

Transfer Pyruvate across inner mitochondrial membrane so it can be used in the TCA cycle

Pyruvate Dehydrogenase (PDH)

converts pyruvate to acetyl-CoA

oxidative decarboxylation

The overall reaction catalyzed by the pyruvate dehydrogenase complex is an __________________

Acetyl-CoA i

is the starting molecule for the TCA Cycle

Pyruvate Dehydrogenase Complex

is a large multienzyme complex comprised of 3 enzymes

Pyruvate

PDH Complex.

E1:

dihydrolipoyl transacetylase

PDH Complex.

E2:

dihydrolipoyl dehydrogenase

PDH Complex.

E3:

• Thiamine pyrophosphate (TPP)

• Lipoic acid

COA-SH

• FAD

• NAD+

5 ASSOCIATED COENZYMES IN PDH COMPLEX

Thiamine pyrophosphate (TPP)

from thiamine (Vitamin B1)

1. Wernicke-Korsakoff Syndrome

2. Beriberi:

Deficiency of Thiamine:

Wernicke encephalopathy

Acute phase: confusion, ataxia, abnormal eye movements

Korsakoff's psychosis

Chronic phase: amnesia (anterograde, retrograde), confabulation

Wet type

cardiovascular presentations (Congestive Heart Failure)

Dry type

peripheral neuropathy

Deficiency of Thiamine:

the ff symptoms causes what?

• Severe malnutrition

• Patients on prolonged intravenous therapy

• Gastrointestinal disorders

• Alcoholics (most common form in developed countries)

Nicotinamide adenine dinucleotide (NAD+)

from Niacin (Vitamin B3)

Pellagra

Deficiency of niacin

Deficiency of niacin

the ff symptoms causes what?

The 3 (or 4) D's

• Diarrhea

• Dermatitis

• Dementia

• (Death)

Flavin adenine dinucleotide (FAD)

from Riboflavin (Vitamin B2)

• Angular Stomatitis • Cheilosis • Glossitis

Deficiency of riboflavin causes

CoA

Requires pantothenic acid (vitamin B5) for synthesis (No deficiency)

Lipoic Acid

-Primarily found protein-bound as Lipoamide

-Not a vitamin

-But 'vitamin-like' in that it acts as a coenzyme

-No deficiency

products ; high energy signals

-Acetyl-CoA

-NADH (high ratio)

-ATP

-cAMP

PDH is t is allostrically inhibited by its __________ and ___________________; namely:

low energy signals;

-Insulin

-NAD+

-CoA

-Ca2+

It is allosterically activated by _____________________; namely:

Pyruvate Dehydrogenase Kinase (PDK)

-Phosphorylates and inactivates PDH (E1 subunit)

Pyruvate Dehydrogenase Phosphatase (PDP)

Dephosphorylates and activates PDH (E1 subunit)

Arsenic Poisoning

Arsenate (an arsenic derivative) forms a stable complex with thiol (SH) groups of lipoic acid

Arsenic Poisoning

Causes:

• Drinking water (naturally found in groundwater)

• Pesticides

• pigmentary skin changes,

• skin cancer

• vomiting and having diarrhea,

• QT prolongation

• garlic breath

Clinical findings of Arsenic Poisoning

PDH Deficiency

Rare deficiency in E1 subunit of PDH

PDH Deficiency

-Most common cause of congenital lactic acidosis

-Pyruvate accumulates, shunted to lactic acid by lactate dehydrogenase

• Substrate availability

• Product inhibition

• Allosteric regulation

3 principal regulated steps of TCA

• Citrate

• ATP

• NADH

• elevated ratios of [NADH]/(NAD*)

Citrate Synthase is inhibited by

ADP

Also controlled by substrate availability: Acetyl CoA, OAA

Citrate Synthase is activated by

• Ca2+ ions

• ADP

Isocitrate Dehydrogenase is activated by

• ATP

• NADH

Isocitrate Dehydrogenase is inhibited by

Ca+ ions

a-Ketoglutarate Dehydrogenase is activated by

• Succinyl CoA

• NADH

• АТР

a-Ketoglutarate Dehydrogenase is inhibited by

Fluoroacetate

Fluorocitrate is competitive inhibitor of aconitase. Causes death

2.5 (or 3)

1 NADH = ________ ATP

1.5 (or 2)

1 FADH = ______ ATP

15

Complete oxidation of a molecule of Pyruvate yields: ____ATP