A cofactor is a non-protein chemical compound that is required for the protein’s biological activity. These proteins are commonly enzymes, and cofactors can be considered “helper molecules” that assist in biochemical transformations. Cofactors can be subdivided into either one or more inorganic ions, or a complex organic or metalloorganic molecule called a coenzyme; most of which are derived from vitamins and from required organic nutrients in small amounts. A coenzyme that is tightly or even covalently bound is termed a prosthetic group. Some sources also limit the use of the term “cofactor” to inorganic substances. An inactive enzyme without the cofactor is called an apoenzyme, while the complete enzyme with cofactor is called a holoenzyme. Some enzymes or enzyme complexes require several cofactors. For example, the multienzyme complex pyruvate dehydrogenase at the junction of glycolysis and the citric acid cycle requires five organic cofactors and one metal ion: loosely bound thiamine pyrophosphate (TPP), covalently bound lipoamide and flavin adenine dinucleotide (FAD), and the cosubstrates nicotinamide adenine dinucleotide (NAD+) and coenzyme A (CoA), and a metal ion (Mg2+). Organic cofactors are often vitamins or are made from vitamins. Many contain the nucleotide adenosine monophosphate (AMP) as part of their structures, such as ATP, coenzyme A, FAD, and NAD+. This common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world. It has been suggested that the AMP part of the molecule can be considered a kind of “handle” by which the enzyme can “grasp” the coenzyme to switch it between different catalytic centers.