BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

SECTION 5. BIOLOGICAL MEMBRANES

All Cells are surrounded by membranes. In addition, nearly all Eukaryotic cells contain Organelles, each enclosed by its own specific membrane. Membranes are responsible for many of The Cell's most vital Functions. The coordinated operation of membrane systems—receptors, Enzymes, and transport mechanisms—helps maintain METABOLISM/37.html">Cellular Homeostasis while enabling a rapid response to environmental changes.

The primary functions of membranes include:

✵ separating the cell from its external environment and forming intracellular compartments;

✵ controlling and regulating The transport of a vast array of substances across the membrane;

✵ participating in intercellular interactions and the transmission of signals into the cell;

✵ converting the energy of dietary Organic compounds into the chemical bond energy of ATP molecules.

I. The Role of Membranes in Metabolism and Their Diversity

While the fundamental principles of structural Organization are similar across all membranes, one of their most striking features is their immense diversity. The membranes of eukaryotic organelles are unique in both composition and function.

Plasma Membrane

The Plasma Membrane, which envelops every cell, determines its size, facilitates the Transport of Small and large molecules into and out of the cell, and maintains ion concentration gradients across the bilayer. It participates in Intercellular Contacts and receives, amplifies, and transduces extracellular signals into the cell. Furthermore, many enzymes that catalyze biochemical reactions are associated with this membrane.

Nuclear Membrane

The nuclear envelope consists of an outer and an inner nuclear membrane. It is punctuated by pores that allow RNA to pass from The Nucleus into the Cytoplasm, and regulatory Proteins to move from the cytoplasm into the nucleus.

The inner nuclear membrane contains specific proteins with binding sites for major nuclear matrix Polypeptides—lamins A, B, and C. An essential function of these proteins is the disassembly of the nuclear envelope during mitosis.

Endoplasmic reticulum (ER) Membrane

The ER membrane features numerous folds and invaginations, forming a continuous surface that encloses an internal space known as the ER lumen. The rough ER is studded with Ribosomes, which synthesize proteins destined for the plasma membrane, the ER itself, the Golgi apparatus, and Lysosomes, as well as secreted proteins. Regions of the ER devoid of ribosomes are termed smooth ER. Here, the final stages of Cholesterol and phospholipid Biosynthesis take place, along with oxidation reactions involving endogenous metabolites and xenobiotics, mediated by membrane-bound enzymes such as cytochrome P₄₅₀, cytochrome P₄₅₀ reductase, cytochrome b₅ reductase, and cytochrome b₅ (see Section 12).

Golgi Apparatus

The Golgi apparatus is a major membrane-bound organelle responsible for the modification, storage, sorting, and trafficking of various substances to their appropriate intracellular compartments or for secretion outside the cell. Specific enzymes within the Golgi membrane, known as Glycosyltransferases, glycosylate proteins at Serine, Threonine, or asparagine amide residues, completing the synthesis of complex Glycoproteins.

Mitochondrial Membranes

Mitochondria are double-membrane-bound organelles specialized for ATP synthesis via Oxidative Phosphorylation. A hallmark of the outer mitochondrial membrane is the presence of high concentrations of porin, a protein that forms aqueous channels. Porin renders the outer membrane freely permeable to inorganic ions, metabolites, and even small proteins (under 10 kDa). It remains impermeable to larger proteins, preventing mitochondrial intermembrane space proteins from leaking into the Cytosol.

The inner mitochondrial membrane is characterized by a high protein content of approximately 70%, which primarily fulfills catalytic and transport functions. Membrane translocases facilitate the selective transfer of substances between the intermembrane space and the matrix, while enzymes participate in electron transport (the Electron Transport Chain) and ATP synthesis. The Structure and function of the enzymes of The electron transport chain are discussed in detail in Section 6.

Lysosomal Membrane

The lysosomal membrane acts as a protective shield separating more than 50 active hydrolytic enzymes—which mediate the Breakdown of Proteins, CARBOHYDRATES, Lipids, and Nucleic Acids—from the rest of the cellular contents. The membrane contains unique proteins, such as an ATP-dependent proton pump that maintains the acidic environment (pH 5) required for The activity of these hydrolytic enzymes (proteases and lipases), as well as transport proteins that allow the degradation products of macromolecules to exit the lysosome. Most lysosomal Membrane Proteins are heavily glycosylated; the carbohydrate moieties lining the inner surface protect them from proteolytic degradation.

A. Structure and Composition of Membranes

Introduction/36.html">Biological Membranes are "ensembles" of lipid and protein molecules held together by non-covalent interactions.

The core of the membrane is formed by a lipid bilayer, which is composed of Phospholipids and Glycolipids. The Lipid Bilayer consists of two rows of lipids with their hydrophobic tails tucked inward, while their hydrophilic groups face outward, contacting the aqueous environment. Protein molecules are, as it were, "dissolved" in the lipid bilayer (Fig. 5-1).

Class="center">Fig. 5-1. Cross-section of a plasma membrane.

1. Structure and properties of Membrane Lipids

Membrane lipids are amphiphilic (amphipathic) molecules, meaning they contain both hydrophilic groups (polar "heads") and aliphatic chains (hydrophobic "tails") that spontaneously form a bilayer. In most eukaryotic cells, they account for approximately 30–70% of the membrane mass (Fig. 5-2). Three MAIN TYPES OF lipids are present in membranes: phospholipids, glycolipids, and cholesterol.

Fig. 5-2. Lipid and protein content in various cellular membranes (%).

The Lipid Composition of membranes varies; the specific amounts of individual lipids are presumably determined by the diverse functions these lipids perform within the membranes.

Phospholipids. All phospholipids can be divided into two groups: Glycerophospholipids and sphingophospholipids. Glycerophospholipids are derivatives of phosphatidic acid. The most abundant glycerophospholipids in membranes are phosphatidylcholines and phosphatidylethanolamines (Fig. 5-3). Eukaryotic Cell membranes contain a vast array of different phospholipids, which are unevenly distributed among various cellular membranes. This Asymmetry applies to the distribution of both polar "heads" (Table 5-1) and acyl residues (Table 5-2).

Table 5-1. Phospholipid composition of cell organelles and hepatocyte plasma membrane

Table 5-2. Fatty acid composition of certain Liver membranes

Each individual glycerophospholipid, such as phosphatidylcholine, is actually represented by dozens of distinct molecular species differing in their fatty acid residues.

Glycerophospholipids with an Inositol polar group account for only 2–8% of all phospholipids in eukaryotic cell membranes. Inositol within phosphatidylinositols can be phosphorylated at C₄ (phosphatidylinositol-4-monophosphate) or at both C₄ and C₅ (phosphatidylinositol-4,5-bisphosphate).

Fig. 5-3. Membrane glycerophospholipids.

Phosphatidylinositol-4,5-bisphosphates predominantly contain stearic or palmitic acid residues (at the glycerol C-1 position) and arachidonic acid residues (at the C-2 position).

Cardiolipins (diphosphatidylglycerols) are specific phospholipids of the inner mitochondrial membrane, built from a glycerol backbone and two phosphatidic acid residues. They are synthesized by enzymes located in the inner mitochondrial membrane and comprise about 22% of its total phospholipids.

Cell Plasma Membranes contain significant amounts of sphingomyelins (Fig. 5-4). Sphingomyelins are based on ceramide, an acylated amino alcohol known as sphingosine. Their polar head group consists of a phosphoric acid residue combined with Choline, ethanolamine, or serine. Sphingomyelins are the major lipids found in the myelin sheath of nerve fibers.

Fig. 5-4. Sphingophospholipids—ceramide derivatives.

Glycolipids. In glycolipids, the hydrophobic moiety is represented by ceramide. The hydrophilic group is a carbohydrate residue attached via a glycosidic bond to the hydroxyl group at the C-1 carbon atom of ceramide (Fig. 5-5). Depending on the length and STRUCTURE OF THE carbohydrate moiety, a distinction is made between cerebrosides, which contain a mono- or oligosaccharide residue, and gangliosides, in which a complex, branched oligosaccharide containing N-acetylneuraminic acid (NANA) is attached to the OH group (see Section 7).

Fig. 5-5. Glycolipids. Gal — galactose; Glc — glucose; NANA (NeuAc) — N-acetylneuraminic or sialic acid.

The polar "heads" of glycosphingolipids are located on the outer surface of plasma membranes. Glycolipids are found in significant amounts in the membranes of Brain cells, erythrocytes, and epithelial cells. Erythrocyte gangliosides from different individuals vary in The structure of their oligosaccharide chains, which exhibit antigenic properties.

Cholesterol. Cholesterol is present in all animal cell membranes. Its molecule consists of a rigid Hydrophobic core and a flexible hydrocarbon chain, with a single hydroxyl group acting as the "polar head" (Fig. 5-6).

Fig. 5-6. Position of a cholesterol molecule in the membrane. The cholesterol molecule is located within the lipid layer of the membrane, parallel to the aliphatic chains of phospho- and glycolipid molecules. The hydroxyl group of cholesterol interacts with the hydrophilic "heads" of these lipids.

For an animal cell, the average cholesterol-to-phospholipid molar ratio is 0.3 — 0.4, but in the plasma membrane this ratio is much higher (0.8 — 0.9). The presence of cholesterol in membranes decreases the mobility of fatty acids, reduces the lateral diffusion of lipids and proteins, and can therefore influence the functions of membrane proteins.

Plant cell membranes lack cholesterol, containing plant Steroids—sitosterol and stigmasterol—instead.

2. Transmembrane Lipid Asymmetry

Every cellular membrane is closed, meaning it has inner and outer surfaces that differ in lipid and protein composition—a feature known as transmembrane (or transverse) asymmetry.

Lipid asymmetry arises primarily because lipids with bulkier polar "heads" tend to reside in the outer monolayer, where the surface area available per polar "head" is larger. Phosphatidylcholines and sphingomyelins are predominantly localized in the outer monolayer, whereas phosphatidylethanolamines and phosphatidylserines are mainly found in the inner one.

In some biological membranes, lipids migrate from one side of the membrane to the other with a relatively high frequency, undergoing "flip-flop" transitions (Fig. 5-7). The movement of lipid molecules is hindered by their polar "heads"; consequently, lipids located on the inner side of the membrane have a relatively high rate of transmembrane migration compared to those on the outer side, which migrate more slowly or may not undergo "flip-flop" transitions at all.

Fig. 5-7. Types of movements of lipid molecules in the membrane bilayer.

3. Membrane Fluidity

Membranes are characterized by fluidity and the ability of lipids and proteins to undergo lateral diffusion. The rate of molecular movement depends on membrane microviscosity, which in turn is determined by the relative content of saturated and Unsaturated fatty acids within the lipids. Microviscosity is lower when unsaturated fatty acids predominate among the lipids, and higher when There is a high content of saturated fatty acids.

The acyl (aliphatic) tails of unsaturated fatty acids contain so-called "kinks" (see Section 8). These "kinks" prevent the molecules from packing too tightly within the membrane, making it looser and, consequently, more "fluid." Membrane fluidity is also affected by the length of the hydrocarbon lipid "tails"; as their length increases, the membrane becomes more "fluid."

4. Functions of Membrane Lipids

In addition to forming the lipid bilayer, membrane phospho- and glycolipids perform several other important functions.

Lipids provide the environment necessary for the functioning of membrane proteins, allowing them to assume their native conformation. Membrane-isolated enzymes stripped of their lipid surroundings generally lose their catalytic activity.

Certain membrane lipids act as precursors of second messengers in hormone signal Transduction. For instance, phosphatidylinositol-4,5-bisphosphate (PIP₂) is hydrolyzed by the enzyme phospholipase C to yield diacylglycerol (DAG), an activator of protein kinase C, and inositol-1,4,5-trisphosphate (IP₃), a regulator of cellular Calcium Homeostasis (Fig. 5-8). DAG, IP₃, protein kinase C, and Ca²⁺ are Components of the inositol phosphate signaling pathway.

Fig. 5-8. Hydrolysis of phosphatidylinositol-4,5-bisphosphate.

Furthermore, some lipids perform an "anchoring" function; for example, specific proteins on the outer cell surface can be attached to phosphatidylinositols via an oligosaccharide (Fig. 5-9). Phosphatidylinositol linked to an oligosaccharide (glycan) is referred to as phosphatidylinositol glycan.

Fig. 5-9. "Anchoring" function of phosphatidylinositol glycans.

Proteins are linked to this molecule (glycan) via phosphoethanolamine. An example of such an "anchored" protein is acetylcholinesterase, which catalyzes the hydrolysis of acetylcholine in the synaptic cleft. This enzyme is anchored to the postsynaptic membrane through covalent attachment to phosphatidylinositolglycan. The release of proteins from the outer cell surface can be triggered by the action of phospholipase C.

Lipids can act as allosteric activators of membrane-bound enzymes. For example, β-hydroxybutyrate dehydrogenase, which is involved in The oxidation of Ketone Bodies (see Section 8), is localized on the inner mitochondrial membrane. The catalytic activity of this enzyme is manifested only in the presence of phosphatidylcholine.

The enzyme protein kinase C catalyzes protein phosphorylation reactions at Serine and threonine amino acid residues. In its inactive form, protein kinase C resides in the cytosol. However, upon cell stimulation (resulting in an elevation of intracellular calcium concentration), the enzyme is rapidly activated by Calcium Ions and associates with the membrane. Functionally active protein kinase C is a complex consisting of an enzyme monomer, a diacylglycerol molecule, one or more Ca²⁺ ions, and four phosphatidylserine molecules.

Creatine kinase, an enzyme that catalyzes The formation of the high-energy compound creatine phosphate (see Section 9). Its activity requires specific interaction with cardiolipin in the inner mitochondrial membrane.