The glycerol-3-phosphate shuttle is a mechanism used in skeletal muscle and the brain that regenerates NAD⁺ from

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

, a by-product of

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

. NADH is a reducing equivalent that stores

electrons The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

generated in the cytoplasm during glycolysis. NADH must be transported into the mitochondria to enter the

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

pathway. However, the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

is impermeable to NADH and only contains a transport system for NAD⁺. Depending on the type of tissue either the glycerol-3-phosphate shuttle pathway or the

malate–aspartate shuttle The malate–aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in euka ...

pathway is used to transport electrons from cytoplasmic NADH into the mitochondria. The shuttle consists of two proteins acting in sequence. Cytoplasmic

glycerol-3-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase (GPDH) is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (a.k.a. glycerone phosphate, outdated) to sn-glycerol 3-phosphate. Glycerol-3-phosphate dehydrogenase serves a ...

(cGPD) transfers an electron pair from NADH to

dihydroxyacetone phosphate Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...

(DHAP), forming glycerol-3-phosphate (G3P) and regenerating the NAD⁺ needed to generate energy via glycolysis. Mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) then catalyzes the oxidation of G3P by

FAD A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period. Fads are objects or behaviors tha ...

, regenerating DHAP in the cytosol and forming FADH₂ in the mitochondrial matrix. In mammals, its activity in transporting reducing equivalents across the mitochondrial membrane is secondary to the malate–aspartate shuttle.

History

The glycerol phosphate shuttle was first characterized as a major route of mitochondrial hydride transport in the flight muscles of blow flies. It was initially believed that the system would be inactive in mammals due to the predominance of

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...

activity over glycerol-3-phosphate dehydrogenase 1 (GPD1) until high GPD1 and GPD2 activity were demonstrated in mammalian

brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...

and pancreatic ß-islets.

Reaction

In this shuttle, the enzyme called cytoplasmic

1 (GPD1 or cGPD) converts

(2) to

glycerol 3-phosphate ''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholi ...

(1) by oxidizing one molecule of NADH to NAD⁺ as in the following reaction: Dihydroxyacetone phosphate to glycerol 3-phosphate en

Glycerol-3-phosphate is converted back to dihydroxyacetone phosphate by an inner membrane-bound mitochondrial

2 (GPD2 or mGPD), this time reducing one molecule of enzyme-bound

flavin adenine dinucleotide In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...

(FAD) to FADH₂. FADH₂ then reduces coenzyme Q (ubiquinone to ubiquinol) whose electrons enter into

. This reaction is irreversible. These electrons bypass Complex I of the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

, making the glycerol-3-phosphate shuttle less energetically efficient compared to oxidation of NADH by Complex I.

References

External links

* http://chemistry.elmhurst.edu/vchembook/601glycolysissum.html {{Webarchive, url=https://web.archive.org/web/20200624183736/http://chemistry.elmhurst.edu/vchembook/601glycolysissum.html , date=2020-06-24 (describes the shuttle in the context of glycolysis) Biochemical reactions Cellular respiration

History

Reaction

See also

References

External links