Pantothenate (Vitamin) : Physiology, Evidence, and Clinical Translation

Pantothenate: The Universal Acyl Carrier at the Core of Energy Metabolism, Acetylcholine Synthesis, and Cellular Stress Adaptation

Pantothenate, vitamin B5, is a water-soluble vitamin that serves as the obligate precursor for the biosynthesis of coenzyme A (CoA) and the acyl carrier protein (ACP). Coenzyme A is the most important acyl group carrier in human metabolism, a thiol-bearing cofactor that activates carboxylic acids as thioesters and facilitates their transfer, condensation, and oxidation in hundreds of reactions that span the tricarboxylic acid cycle, fatty acid oxidation and synthesis, ketogenesis, cholesterol synthesis, and the acetylation of proteins and small molecules. The prosthetic group of ACP, a component of the fatty acid synthase complex, is a phosphopantetheine arm that swings the growing acyl chain from one catalytic site to the next. Pantothenate is not synthesized by human cells; it is obtained from the diet and transported into cells by a sodium-dependent multivitamin transporter that also carries biotin and lipoate. This monograph is written for the clinician and scientist who seek to understand pantothenate not as a generic B vitamin, but as the foundational molecule for a cofactor system that is essential for the extraction of energy from all macronutrients, for the synthesis of the neurotransmitter acetylcholine, for the post-translational modification of proteins by acylation, and for the metabolic flexibility that permits the organism to transition between fed and fasted states. We dissect the architecture of the CoA molecule and its biosynthetic pathway, grade the clinical evidence for pantothenate supplementation, and map the unresolved questions about the regulation of intracellular CoA concentration in health and disease.

---

Part 1. The Structural and Chemical Identity of Pantothenate

Pantothenate is a dihydroxy-dimethyl-butyric acid derivative linked to beta-alanine through an amide bond. Its chemical name is D-pantothenic acid, and it is composed of pantoic acid, a branched-chain hydroxy acid, and beta-alanine, a non-proteinogenic amino acid. The biologically active form is the D-isomer; the L-isomer is not utilized. Pantothenate is a pale yellow, viscous oil in its free acid form, but it is most commonly available as the calcium salt, calcium pantothenate, a white, crystalline, water-soluble powder that is stable to heat but labile to acid and alkali.

The functional essence of pantothenate is realized not in the free vitamin but in its fully elaborated cofactor form, coenzyme A. The CoA molecule is a modular assembly of an adenine nucleotide, a diphosphate bridge, a pantothenate moiety, and a terminal cysteamine residue. The business end of the molecule, the thiol group of the cysteamine, is the site of acyl group attachment. The thioester bond that links an acyl group to the CoA thiol is a high-energy linkage, with a free energy of hydrolysis comparable to that of the phosphoanhydride bonds of ATP. This makes acyl-CoA thioesters activated acyl donors for a wide range of nucleophilic acceptors, a chemical principle that underlies the central role of CoA in metabolism.

1A. The Biosynthetic Impossibility: Why Pantothenate Is Essential

Plants, fungi, and bacteria synthesize pantothenate from pantoic acid and beta-alanine. Pantoic acid is derived from alpha-ketoisovalerate, an intermediate in the biosynthesis of the branched-chain amino acids valine and leucine. Beta-alanine is derived from the decarboxylation of aspartate. The condensation of pantoic acid and beta-alanine is catalyzed by pantothenate synthetase. This pathway is absent in humans. Pantothenate is therefore a vitamin, and the recommended adequate intake for adults is 5 milligrams per day. Dietary sources are ubiquitous, and the name "pantothenate" derives from the Greek "pantothen," meaning "from everywhere." Rich sources include liver, kidney, egg yolk, whole grains, legumes, and royal jelly. Meat, poultry, and fish are good sources. Freezing and canning of foods result in significant losses of pantothenate.

1B. The Biosynthesis of Coenzyme A: From Vitamin to Universal Acyl Carrier

The conversion of pantothenate to CoA proceeds through a series of five enzymatic reactions that are conserved from bacteria to humans. First, pantothenate kinase (PANK), the rate-limiting enzyme, phosphorylates pantothenate at the primary hydroxyl group to yield 4'-phosphopantothenate. Second, phosphopantothenoylcysteine synthetase condenses 4'-phosphopantothenate with cysteine, consuming ATP and generating phosphopantothenoylcysteine. Third, phosphopantothenoylcysteine decarboxylase removes the carboxyl group of the cysteine moiety, yielding 4'-phosphopantetheine. Fourth, phosphopantetheine adenylyltransferase transfers an adenosyl monophosphate group from ATP to the phosphate of 4'-phosphopantetheine, forming dephospho-CoA. Fifth, dephospho-CoA kinase phosphorylates the ribose 3'-hydroxyl of the adenosine moiety, yielding the final product, CoA.

This pathway is tightly regulated, and the first step, catalyzed by PANK, is the primary control point. There are four human PANK isoforms, PANK1alpha, PANK1beta, PANK2, and PANK3, with distinct tissue distributions and regulatory properties. PANK1beta, the predominant isoform in the liver, is feedback-inhibited by CoA and by acyl-CoAs, a classic end-product inhibition that matches the rate of CoA synthesis to cellular demand. Mutations in PANK2 are the cause of pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder characterized by iron accumulation in the basal ganglia and progressive dystonia and dementia. The pathogenesis of PKAN involves a failure of CoA synthesis in the brain, leading to mitochondrial dysfunction, oxidative stress, and the accumulation of abnormal lipid species.

---

Part 2. The Coenzyme A Biology: The Central Acyl Carrier of Metabolism

The functional biology of pantothenate is the biology of CoA and its acyl derivatives. The concentration of CoA in the cell is in the range of 50 to 500 micromolar, and the CoA pool is partitioned between free CoA, short-chain acyl-CoAs (acetyl-CoA, propionyl-CoA, succinyl-CoA), medium-chain acyl-CoAs, and long-chain acyl-CoAs. The distribution of acyl groups among the CoA pool is a reflection of the metabolic state of the cell and a determinant of the activity of CoA-dependent enzymes.

2A. Acetyl-CoA: The Metabolic Crossroads

Acetyl-CoA is the central intermediate of energy metabolism. It is the product of the pyruvate dehydrogenase complex, which links glycolysis to the tricarboxylic acid cycle, and of the beta-oxidation of fatty acids, which breaks down long-chain fatty acyl-CoAs to generate acetyl-CoA, NADH, and FADH2. Acetyl-CoA cannot cross the inner mitochondrial membrane. For the carbon of acetyl-CoA to be exported from the mitochondrion to the cytoplasm for fatty acid synthesis or cholesterol synthesis, it must be converted to citrate by citrate synthase, transported across the membrane, and cleaved by ATP-citrate lyase back to acetyl-CoA and oxaloacetate. The cytoplasmic acetyl-CoA pool is the substrate for the synthesis of fatty acids, cholesterol, and ketone bodies in the liver. The acetyl group of acetyl-CoA is also the donor for the acetylation of proteins, including histones, a post-translational modification that regulates chromatin structure and gene expression, and for the synthesis of the neurotransmitter acetylcholine in cholinergic neurons.

Acetylcholine is synthesized from choline and acetyl-CoA in a reaction catalyzed by choline acetyltransferase. The acetyl-CoA used for acetylcholine synthesis is derived from the pyruvate dehydrogenase complex in the mitochondrion and is transported to the cytoplasm, potentially as citrate. The availability of acetyl-CoA, and therefore of pantothenate, is a potential determinant of the rate of acetylcholine synthesis in the brain, a concept that underlies the investigation of pantothenate as a cognitive enhancer and as an agent for the treatment of neurodegenerative cholinergic deficits.

2B. Fatty Acid Oxidation and Synthesis

The oxidation of fatty acids in the mitochondrial matrix is a CoA-dependent process. Long-chain fatty acids are activated to their acyl-CoA thioesters by acyl-CoA synthetases on the outer mitochondrial membrane, consuming ATP. The acyl-CoA is then transported into the mitochondrion via the carnitine shuttle, a process that involves the transient transfer of the acyl group from CoA to carnitine and back to CoA. The acyl-CoA in the matrix is then degraded by the beta-oxidation spiral, a sequence of four reactions that sequentially removes two-carbon units as acetyl-CoA. Each cycle of beta-oxidation requires a molecule of CoA to accept the acyl group. The CoA pool is therefore a kinetic determinant of the rate of fatty acid oxidation.

The synthesis of fatty acids in the cytoplasm requires a distinct CoA-dependent step: the carboxylation of acetyl-CoA to malonyl-CoA by acetyl-CoA carboxylase, and the transfer of the malonyl group from CoA to the ACP prosthetic group of the fatty acid synthase. The phosphopantetheine arm of ACP, which is derived from CoA, is the flexible tether that moves the growing fatty acyl chain from one active site to the next within the fatty acid synthase dimer. The synthesis of ACP requires pantothenate, and the availability of pantothenate can influence the rate of fatty acid synthesis.

2C. Ketogenesis, Cholesterol Synthesis, and the Mevalonate Pathway

In the liver, during fasting or in uncontrolled diabetes, the mitochondrial acetyl-CoA pool exceeds the capacity of the tricarboxylic acid cycle, and the excess acetyl-CoA is diverted to the synthesis of ketone bodies: acetoacetate and beta-hydroxybutyrate. The ketogenic pathway begins with the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA, catalyzed by acetoacetyl-CoA thiolase. The addition of a third acetyl-CoA by HMG-CoA synthase generates 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is cleaved by HMG-CoA lyase to acetoacetate and acetyl-CoA.

In the cytoplasm, the same HMG-CoA molecule is the substrate for HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis and the target of the statin class of drugs. The mevalonate pathway that produces cholesterol, and the branch pathways that produce ubiquinone, dolichols, and the isoprenoid modifications of small GTPases, all begin with HMG-CoA. The entire architecture of isoprenoid and sterol biosynthesis is built on a CoA-dependent condensation reaction, and pantothenate is the ultimate source of the CoA that carries the acyl groups through the pathway.

---

Part 3. The Non-Metabolic Biology of Coenzyme A: Acylation and Signaling

Beyond its role as a soluble acyl carrier, CoA is the donor for the acylation of proteins, a post-translational modification that regulates protein localization, activity, and interactions.

3A. Protein Acetylation and Epigenetic Regulation

The acetylation of the epsilon-amino group of lysine residues on histones is a fundamental epigenetic mark that regulates chromatin structure and gene transcription. The acetyl donor for histone acetyltransferases is acetyl-CoA. The concentration of acetyl-CoA in the nucleus, which is determined by the metabolic state of the cell and by the activity of the enzymes that generate acetyl-CoA locally, influences the global pattern of histone acetylation. In conditions of nutrient abundance, when acetyl-CoA is plentiful, histone acetylation is increased, promoting a chromatin state that is permissive for transcription. In conditions of nutrient scarcity, acetyl-CoA is depleted, histone acetylation is reduced, and gene expression is constrained. This is a direct mechanism by which cellular metabolic state, and by extension pantothenate status, is coupled to the regulation of gene expression.

The acetylation of non-histone proteins, including transcription factors, metabolic enzymes, and cytoskeletal proteins, is also an acetyl-CoA-dependent process. The acetylation of p53, the tumor suppressor, regulates its stability and transcriptional activity. The acetylation of tubulin in the microtubule network influences the trafficking of vesicles and organelles. The acetylation of the mitochondrial enzymes of fatty acid oxidation and the TCA cycle is a major mechanism of metabolic regulation, and the acetyl-CoA that donates the acetyl group is generated within the mitochondrion itself.

3B. Protein Acylation with Longer-Chain Acyl-CoAs

The acylation of proteins is not limited to acetyl groups. Long-chain acyl-CoAs, including palmitoyl-CoA and myristoyl-CoA, are substrates for the N-terminal myristoylation and the cysteine palmitoylation of proteins. Myristoylation, a co-translational modification, targets proteins to the plasma membrane. Palmitoylation, a reversible post-translational modification, regulates the membrane association and the trafficking of peripheral membrane proteins, including the Src family kinases, the G-protein alpha subunits, and the neuronal scaffolding proteins. The CoA thioesters of the long-chain fatty acids are the donors for these modifications, and pantothenate is the obligate precursor of the CoA that carries them.

---

Part 4. The Clinical Taxonomy of Pantothenate Insufficiency

Isolated dietary pantothenate deficiency is exceptionally rare, a testament to the ubiquity of the vitamin in the food supply. The clinical manifestations of pantothenate deficiency have been described in experimental human depletion studies and in cases of severe generalized malnutrition.

4A. Experimental Human Deficiency and the Burning Feet Syndrome

During World War II, prisoners of war in the Far East who were fed a diet deficient in multiple B vitamins developed a syndrome of painful burning and numbness in the feet, known as the "burning feet syndrome" or "nutritional melalgia." The syndrome was partially responsive to pantothenate supplementation, though the deficiency was never isolated to pantothenate alone. Experimental pantothenate deficiency, induced in human volunteers by the administration of the pantothenate antagonist omega-methyl pantothenate, produced a constellation of symptoms including fatigue, malaise, abdominal distress, sleep disturbance, and a distressing paresthesia and dysesthesia in the feet. The peripheral neurological symptoms are consistent with a failure of CoA-dependent energy metabolism in the peripheral nerve and with a failure of acetylcholine synthesis in the cholinergic autonomic neurons that innervate the microvasculature of the skin. The clinical syndrome of isolated pantothenate deficiency is a historical and experimental entity, not a common clinical presentation.

4B. Pantothenate in the Context of Acne Vulgaris: A Clinical Enigma

The use of pantothenate, and particularly of its alcohol analog panthenol, in the treatment of acne vulgaris is a persistent theme in the nutraceutical and dermatological literature. The rationale is that pantothenate, by increasing the CoA pool in the sebocyte, could reduce the rate of fatty acid and cholesterol synthesis and thereby reduce the production of sebum, the oily secretion of the sebaceous gland that is a contributor to the pathogenesis of acne. A small number of uncontrolled clinical studies and a much larger body of anecdotal experience suggest that high-dose pantothenate, typically 2 to 10 grams per day, can reduce the number and severity of acne lesions. The evidence is not of a quality that permits a definitive recommendation, but the safety of pantothenate at these high doses is well-established, and the intervention is a reasonable consideration for patients who are intolerant of or who prefer to avoid standard topical and systemic acne therapies. The mechanism of action has not been confirmed in human sebaceous glands, and the possibility of a placebo effect, which is substantial in acne trials, cannot be excluded.

4C. Pantothenate, Wound Healing, and the Post-Surgical State

Pantothenate is a cofactor for the synthesis of fatty acids and cholesterol that are required for the formation of new cell membranes in proliferating fibroblasts and keratinocytes. The demand for CoA-dependent processes in wound healing is high. Topical dexpanthenol, the alcohol analog of pantothenate, is widely used in wound care and in the management of post-surgical wounds and dermatological procedures. Dexpanthenol is converted to pantothenate in the skin and then to CoA. The clinical evidence for a benefit of topical dexpanthenol in wound healing is derived from controlled clinical trials in specific surgical and dermatological contexts, including the management of the nasal mucosa after surgery and the treatment of superficial skin injuries. The use of oral pantothenate to support wound healing from the systemic side is a rational extrapolation, but the clinical evidence is not as robust as that for the topical formulation.

---

Part 5. The Evidence Mapped by Quality and Clinical Application

The clinical evidence for pantothenate is a mixture of solid biochemical rationale, historical clinical observation, and a limited number of controlled trials.

5.1. Pantothenate and Acetylcholine Synthesis: A Cognitive Hypothesis

The dependence of acetylcholine synthesis on the availability of acetyl-CoA, and the potential for pantothenate to increase the neuronal acetyl-CoA pool, has generated interest in pantothenate as a cognitive enhancer and as an adjunctive treatment for Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease holds that the degeneration of cholinergic neurons in the basal forebrain leads to a deficit in acetylcholine in the hippocampus and cortex, which is responsible for the cognitive impairment. The standard pharmacological approach is the inhibition of acetylcholinesterase, the enzyme that degrades acetylcholine, to increase its synaptic concentration. An alternative or complementary approach is to increase the synthesis of acetylcholine by providing its precursors, choline and acetyl-CoA. Pantothenate, as the precursor of the CoA that is required for acetyl-CoA synthesis, is a component of this precursor-loading strategy.

A small number of clinical studies have examined the effect of pantothenate, alone or in combination with choline, on cognitive function in the elderly and in patients with dementia. The results are inconclusive, and the quality of the studies is not sufficient to support a clinical recommendation. The concept of precursor loading for neurotransmitter synthesis is a valid pharmacological principle, but the application to pantothenate and acetylcholine has not been translated into an evidence-based therapy.

5.2. Pantothenate in the Management of Dyslipidemia

The role of pantothenate in the synthesis of fatty acids and cholesterol has led to the investigation of pantothenate analogs, particularly pantethine, the disulfide dimer of pantetheine, as lipid-modifying agents. Pantethine is not pantothenate; it is a distinct compound that is metabolized to two molecules of pantetheine, which are then converted to CoA. A series of clinical trials, primarily conducted in the 1980s and 1990s, demonstrated that pantethine, at doses of 600 to 1200 milligrams per day, reduced total and LDL cholesterol and triglycerides in patients with hyperlipidemia. The magnitude of the effect is modest, a 10 to 20 percent reduction in LDL cholesterol, and the mechanism is not fully defined but likely involves an alteration in the hepatic metabolism of lipoproteins. Pantethine is a non-prescription nutraceutical that is available for the management of mild to moderate dyslipidemia, particularly in patients who are intolerant of statins.

5.3. Topical Dexpanthenol in Wound Care and Dermatology

The evidence for topical dexpanthenol is more robust than that for systemic pantothenate. Dexpanthenol-containing ointments, creams, and nasal sprays are standard agents for the management of superficial wounds, burns, and post-surgical skin care. The mechanism is the conversion of dexpanthenol to pantothenate and then to CoA in the skin, supporting the proliferation and migration of fibroblasts and keratinocytes and the synthesis of the lipids that form the epidermal barrier. The clinical use of topical dexpanthenol is supported by controlled trials in specific contexts, including the management of the nasal mucosa after functional endoscopic sinus surgery and the treatment of diaper dermatitis in infants.

---

Part 6. A Clinical Dosing Compendium

The dosing of pantothenate is indication-specific, and the therapeutic window is wide.

6.1. Evidence-Based and Guideline-Supported Protocols

Nutritional Supplementation. The adequate intake of 5 milligrams per day for adults is the physiological requirement. A standard multivitamin typically contains 5 to 10 milligrams of pantothenate, an amount that is sufficient to maintain tissue CoA pools in a healthy individual.

Acne Vulgaris. The high-dose pantothenate regimen for acne, based on the clinical experience of a small number of practitioners, is 2 to 10 grams per day, administered orally in divided doses. The initial dose is typically 2 to 3 grams per day, titrated upward as tolerated. The therapy is continued for a trial period of 3 to 6 months, and if a response is observed, the dose is maintained or gradually reduced to the lowest effective level. The safety of this regimen is supported by decades of clinical use, but the efficacy is not established by randomized controlled trials. The patient must be informed of the unproven nature of the therapy and of the potential for gastrointestinal upset and diarrhea at the higher doses.

6.2. Theoretical and Postulated Dosing Frameworks

Cognitive Support and Cholinergic Enhancement. Rationale: to increase the neuronal acetyl-CoA pool and to support the synthesis of acetylcholine in the cholinergic neurons of the basal forebrain. Postulate: a dose of 300 to 600 milligrams of pantothenate, three times daily, in combination with a choline source such as citicoline or alpha-GPC, in patients with mild cognitive impairment or early Alzheimer's disease. The primary endpoint would be the change in a validated cognitive assessment scale over 6 to 12 months. This is an experimental protocol, and the clinical evidence is insufficient to support its use outside of a clinical trial.

Systemic Support for Wound Healing. Rationale: to provide the CoA precursor that is required for the synthesis of new cell membranes in proliferating tissue at the wound site. Postulate: a dose of 1 to 2 grams of pantothenate per day, administered orally in divided doses, for 2 to 4 weeks following major surgery or traumatic injury, as an adjunct to standard wound care and nutritional support. The primary endpoint would be the time to complete wound closure. This is a supportive nutritional measure, not a primary therapeutic intervention.

Pantethine for Dyslipidemia. The standard dose of pantethine is 300 milligrams, two to four times daily, for a total daily dose of 600 to 1200 milligrams. The lipid profile should be monitored at baseline and after 3 to 6 months of therapy.

6.3. Universal Principles Governing Pantothenate Supplementation

Pantothenate Is Not Rate-Limiting Under Normal Conditions. The ubiquity of pantothenate in the diet and the saturation of the PANK enzyme at low intracellular pantothenate concentrations mean that the CoA pool is not normally limited by pantothenate availability. The therapeutic use of high-dose pantothenate is based on the hypothesis that, in specific disease states or in tissues with exceptionally high CoA demand, the PANK enzyme is not fully saturated, and an increase in substrate availability can drive an increase in CoA synthesis. This hypothesis has not been directly tested in human tissues.

Pantethine Is Not Pantothenate. The clinical evidence for pantethine as a lipid-modifying agent does not translate to an effect of pantothenate on the lipid profile. The disulfide dimer is a distinct pharmacological entity with a distinct metabolic fate.

Topical Dexpanthenol Is a Different Route and Indication. The conversion of topical dexpanthenol to CoA in the skin is a local effect that does not require systemic absorption. The efficacy of topical dexpanthenol in wound healing does not predict an effect of oral pantothenate on the same endpoint.

---

Part 7. The Unresolved Frontier

Three specific questions define the current limit of pantothenate science.

Does High-Dose Pantothenate Increase Neuronal Acetyl-CoA and Acetylcholine Synthesis in the Human Brain? The precursor-loading hypothesis is mechanistically sound, but it has never been tested directly in the human brain. The development of magnetic resonance spectroscopy methods to measure the rate of acetylcholine synthesis in vivo, and the application of these methods to a trial of high-dose pantothenate with or without choline, would resolve this fundamental question.

What Is the Mechanism of the Putative Anti-Acne Effect of Pantothenate? The observation that gram doses of pantothenate can reduce sebum production and improve acne is supported by clinical anecdotes and small studies, but the molecular mechanism in the human sebocyte is unknown. The direct measurement of CoA levels, fatty acid synthesis, and sebum production in the sebaceous glands of patients treated with high-dose pantothenate would either validate the sebum-suppression hypothesis or point to an alternative mechanism, such as an anti-inflammatory effect.

Why Is the Brain Exquisitely Vulnerable to a Defect in the PANK2 Isoform? Pantothenate kinase-associated neurodegeneration is caused by mutations in the PANK2 gene, yet the other three PANK isoforms are expressed in the brain. The specific vulnerability of the basal ganglia to PANK2 deficiency, and the peculiar accumulation of iron that characterizes the disease, suggests that the PANK2 isoform serves a specialized function in the mitochondrion or in a specific neuronal population that cannot be compensated by the other isoforms. The identification of this function is essential to understanding the pathogenesis of PKAN and to the development of a rational therapy, which could include high-dose pantothenate to drive flux through the residual PANK2 activity.

---

Part 8. Synthesis for an Evidence-Based Approach

Pantothenate is a vitamin whose biological significance is realized entirely through its conversion to coenzyme A and the acyl carrier protein. It is the precursor of the thiol cofactor that carries the acyl groups that fuel the tricarboxylic acid cycle, that are broken down to generate ATP, that are assembled into the lipids of cell membranes and the cholesterol of steroid hormones, and that are transferred to proteins to regulate their function and location. The name "pantothenate" captures its ubiquity in the diet, and its deficiency is correspondingly rare.

The clinical use of pantothenate is confined to a small number of specific indications. High-dose pantothenate for acne vulgaris is a therapy in search of an evidence base, but its safety and the clinical experience of a subset of dermatologists and patients keep it in the conversation as a second-line or adjunctive option. Pantethine, the disulfide dimer of the pantothenate metabolite, has a defined role as a nutraceutical for the management of mild dyslipidemia. Topical dexpanthenol is a well-established agent for wound care and dermatological procedures.

The most profound insights that pantothenate biology offers are not about the vitamin itself but about the central role of CoA and its thioester derivatives in the regulation of metabolism and gene expression. The acetylation of histones by acetyl-CoA links nutrient availability to the epigenome. The acylation of proteins with long-chain fatty acyl-CoAs determines their membrane localization and their signaling function. The discovery of the four human PANK isoforms and the recognition that mutations in PANK2 cause a devastating neurodegenerative disease reveal that the regulation of CoA synthesis is a tissue-specific and compartment-specific process that is essential for the function of the most metabolically demanding organ in the body. The investigation of pantothenate and its cofactor progeny is the investigation of the acyl economy of the cell, and the frontier of this field is the understanding of how the cell senses and regulates its CoA pool to adapt to metabolic stress and to support the specific functions of specialized tissues.